Clinical Therapeutics/Volume 37, Number 2, 2015
Original Research
Single- and Multiple-dose Pharmacokinetics of Samidorphan, A Novel Opioid Antagonist, in Healthy Volunteers Ryan Turncliff, PhD; Lauren DiPetrillo, PhD; Bernard Silverman, MD; and Elliot Ehrich, MD Alkermes, Inc, Waltham, Massachusetts ABSTRACT Purpose: Samidorphan (3-carboxamido-4-hydroxy naltrexone) is a novel opioid receptor antagonist that is currently in clinical development. The oral dose pharmacokinetics, safety, and tolerability of samidorphan were evaluated in 2 double-blind, placebo-controlled, randomized studies in healthy adults. Methods: The first study investigated single, ascending doses of 3.7 to 55.7 mg of samidorphan in 16 healthy adults; the second study evaluated multiple ascending doses of 10 or 20 mg of samidorphan administered for 7 days in 30 healthy adults. Findings: Across the two studies, 39 of 46 subjects were male; 32 were white, 11 were black, and 3 were hispanic. Mean age was 34.9 years and mean weight was 84.2 kg. In both studies, samidorphan was rapidly absorbed, with a Tmax of 1 hour, and AUC increased with increasing dose. Samidorphan plasma levels declined in a monoexponential manner, with a half-life of 7 to 9 hours. After multiple doses, steady state was approached by day 6 and achieved by day 7 after the 10-mg dose, but steady state was not reached for the 20-mg dose. Accumulation was low, with accumulation ratios o1.65. In both studies, samidorphan was generally well tolerated, with somnolence reported as the most common adverse event. Implications: In these single- and multiple-dose studies in healthy volunteers, samidorphan exhibited a pharmacokinetic profile consistent with once-daily dosing.ClinicalTrials.gov identifier: NCT00800319. (Clin Ther. 2015;37:338–348) & 2015 Elsevier HS Journals, Inc. All rights reserved. Accepted for publication October 2, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.10.001 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
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Key words: multiple ascending dose trial, opioid receptor antagonist, pharmacokinetics, safety, samidorphan, single ascending dose trial, tolerability.
INTRODUCTION Mu opioid receptor antagonists, such as naltrexone and naloxone, were developed to counteract the negative adverse effects of opioids. Opioid receptor antagonists have demonstrated clinical efficacy for the treatment of alcohol dependence, opioid dependence, and opioid overdose.1–6 However, the pharmacokinetic (PK) properties of oral naltrexone and naloxone have restricted their clinical utility.2–4 Naloxone has a rapid onset of action but low oral bioavailability that limits oral administration. Although this is beneficial for the treatment of opioid overdose, it reduces the benefits of naloxone for the long-term treatment of drug dependence. Similarly, naltrexone has low oral bioavailability due to its high first-pass metabolism.7 Samidorphan (3-carboxamido-4-hydroxy naltrexone) is a novel opioid receptor antagonist with high affinity and functional activity at the mu opioid receptor.8,9 Samidorphan is structurally related to the mixed opioid receptor antagonist naltrexone. In nonclinical rodent studies, oral administration of samidorphan (previously described as RDC-0313 or ALKS 33) reversed morphine-induced analgesia for 44 hours, supporting its ability to block opioid receptors10,11 and significantly reduced alcohol drinking in rats.12 The pharmacodynamic effects of Scan the QR Code with your phone to obtain FREE ACCESS to the articles featured in the Clinical Therapeutics topical updates or text GS2C65 to 64842. To scan QR Codes your phone must have a QR Code reader installed.
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R. Turncliff et al. samidorphan in animal species revealed a profile different from naltrexone.12,13 The in vitro metabolic profile and in vivo PK characteristics of samidorphan in animals were conducive to use as an oral formulation.14,15 After oral administration, samidorphan was rapidly absorbed, with a Tmax of 2 hours. The absolute bioavailability varied across species, with low oral exposure observed in the rat and higher exposure in the dog and monkey. Although the half-life of samidorphan was 2.0 hours in the rat and dog studies,15 in vitro metabolism experiments suggested a prolongation of the half-life of samidorphan in humans.14 After assessment of the safety profile in nonclinical species, the safety and therapeutic potential of samidorphan were assessed in humans. The purpose of the first-in-human study (study 1) was to investigate the acute safety, tolerability, and PK properties of samidorphan after oral administration of single ascending doses of 3.7 to 55.7 mg in healthy adults. The second Phase I study (study 2) investigated the safety, tolerability, and PK properties of samidorphan after daily dosing for 7 days with 10 or 20 mg in healthy adults.
SUBJECTS AND METHODS Each study protocol and the informed consent forms were approved by local ethics committees and institutional review boards, and each subject provided written informed consent before study participation. All subjects were free to withdraw from the study for any reason at any time. Both studies were conducted in compliance with the principles of the Declaration of Helsinki and current International Conference on Harmonisation Guideline for Good Clinical Practice.
Study Subjects In both studies, healthy male and female adults between the ages of 18 and 65 years (study 1) or 18 and 55 years (study 2) with a body mass index (BMI) of Z19.0 kg/m2 and r30.0 kg/m2, with a minimum weight of 50 kg, were eligible. Subjects were required to have no clinically significant medical illness and a normal physical examination, ECG, and clinical laboratory values. All subjects were required to practice an effective method of contraception. Results of urine drug screenings had to be negative both at screening and at admission to the study facility, and a negative hepatitis panel and HIV antibody screen were also required. Subjects with a known allergy or hypersensitivity to opioid antagonists or quinine were excluded. Subjects
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were excluded if they had a history of alcohol or drug dependence (excluding nicotine or caffeine) within the previous 2 years based on criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision.16 Subjects taking chronic medications or likely to require medications during the study were excluded. Subjects also were excluded for use of any prescription or over-the-counter medication, including natural health products (with the exception of prescription contraceptives or hormonal replacements, acetaminophen, ibuprofen, or multivitamins), within 14 days before the first study drug dose; ingestion of alcohol-, caffeine-, or xanthine-containing products within 24 hours before study drug administration; or participation in a clinical trial of a pharmacologic agent within 30 days of screening. Subjects were also excluded if they had donated blood within 60 days of screening.
Study Design Study 1 was a single-center, randomized, doubleblind, placebo-controlled, ascending-dose study. This study consisted of 1 screening visit, 5 dosing visits, and 1 follow-up visit. After successfully completing screening evaluations, 16 consenting, eligible subjects were randomly assigned to 1 of 8 dosing sequences consisting of 5 administrations of an oral solution of either ascending doses of samidorphan (3–4 doses per subject) or volume-matched placebo (1–2 doses per subject). A total of 12 subjects were to receive samidorphan and 4 subjects were to receive placebo at each dose level. As such, each subject served as his or her own placebo control with regard to the safety assessments of samidorphan. A minimum 7-day washout period separated each dosing visit. Dosing of cohorts was staggered to allow a blinded review of safety data (clinical observations and clinical chemistry) to occur before dosing the next cohort; a comprehensive blinded safety review of data obtained for all subjects was conducted before dose escalation. Each dosing visit required a 60-hour inpatient stay. Subjects were admitted to the study facility the morning before each dosing visit and were required to fast overnight before study drug administration. Subjects were discharged from the facility after the 36-hour postdose assessments for each visit were completed. All doses were prepared by an unblinded pharmacist and administered by the blinded study investigator or a designated staff member. Samidorphan doses of 3.7, 11, 18.6, 37.2, and 55.7 mg (equivalent to samidorphan malate salt doses of
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Clinical Therapeutics 5, 15, 25, 50, and 75 mg) were given as a solution of 2 mg/mL and the placebo as a solution of 0.1 g/L quinine sulfate to mask the bitter taste, together with 240 mL of water. Subjects were fasted from 8 hours before until 4 hours after study drug administration, although water ad libitum was allowed. A final follow-up visit occurred 7 days after the last dosing visit. The 3.7-mg starting dose was selected based on the results of safety studies in nonclinical species showing that the highest doses with no observed adverse events (AEs) ranged from 3 to 10 mg/kg (human-equivalent dose of 100 to 300 mg based on a 60-kg human) (data on file). The application of a 10-fold safety factor translated into a maximum safe recommended starting dose for humans of between 10 and 30 mg of samidorphan. The starting dose used in this study, therefore, represented a 41/10th reduction of the dose that did not result in observable AEs (on the basis of body weight) in the most sensitive nonclinical species. Study 2 was a single-center, randomized, doubleblind, placebo-controlled, multiple-dose study. This study consisted of 3 clinic visits, including a screening visit, 1 study drug inpatient dosing visit, and 1 followup visit. After a screening visit, subjects were randomized to receive 7 consecutive daily 10 mg doses of samidorphan or placebo in a 4:1 ratio. After an interim safety review, a second group of subjects were randomized to receive either 20 mg of samidorphan or placebo in the same 4:1 ratio for 7 consecutive days. Subjects remained at the study facility throughout the 9-day dosing and assessment period, beginning on the evening before dose 1 until after the completion of the 36-hour PK sampling time point after dose 7. All doses were prepared by an unblinded pharmacist and administered by the blinded study investigator or a designated staff member. Samidorphan was administered as an oral solution (2 mg/mL in water) at doses of 10 or 20 mg via an oral dosing syringe. Placebo (0.01% quinine sulfate solution, 0.01 g/L) was administered as an oral solution via an oral dosing syringe. Subjects were fasted overnight for at least 10 hours before dosing until 4 hours postdose on day 1 and again on the evening before dose 7. During both of these fasting periods, water was allowed ad libitum until 1 hour predose and otherwise restricted until the end of the fasting period. A total of 200 mL of water was allowed immediately postdose but otherwise was restricted postdose until the end of the fasting period. On days 2 through 6, overnight fasting was not
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required, but dosing occurred before the morning meal. A final follow-up visit occurred 14 days after discharge from the study facility.
Sample Collection For study 1, venous blood samples (4 mL) for samidorphan levels were collected on each dosing day at the following time points: predose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours postdose. For study 2, venous blood samples (4 mL) for samidorphan levels were collected on day 1 at predose and at 0.25, 0.5, 1, 2, 4, 8, and 12 hours postdose. Trough blood samples were collected immediately before dosing on days 2 through 6. On day 7, blood samples were collected at predose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours postdose. A final blood sample was taken at the follow-up visit (approximately day 21). Blood samples were collected into tubes containing potassium EDTA, gently mixed, and stored on ice until sample processing. Plasma was separated by centrifugation (2000 rpm, 15 minutes, 41C) within 60 minutes of sample collection. Plasma samples were stored frozen at –701C until subsequent bioanalytical analysis.
Sample Analysis Plasma was analyzed for samidorphan by using a validated HPLC-MS/MS method with an assay range of 0.25 to 100 ng/mL. Quantification was performed by using quadratic weighted 1/ regression analysis of peak-area response ratio (analyte/internal standard) versus nominal concentration. Calibration standards were prepared fresh daily by using potassium EDTA human plasma matrix. Precision and accuracy were evaluated by analyzing quality control (QC) samples at the lower limit of quantitation (LLOQ; 0.25 ng/mL) and at a low QC (0.75 ng/mL), a mid-QC (12.5 ng/mL), and a high QC (80.2 ng/mL). Precision was expressed as the %CV of each QC concentration. Accuracy was assessed as the proportional difference from the theoretical analyte concentration. Interassay accuracy at the 3 QC levels ranged from 0.8% to 4.6% above the percent theoretical, with the exception of at the LLOQ, which was 12.4%. Interassay precision was r10.0%, except at the LLOQ, which was 13.9%.
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PK Analysis PK analysis was performed according to WinNonlin Professional version 5.2 (Pharsight Corporation, Mountain View, California) by using noncompartmental analysis and actual elapsed time from dosing. The PK parameters determined from plasma samidorphan concentrations versus time data after single-dose administration included Cmax and Tmax, both of which were determined directly from experimental observations. The AUC0–last values were calculated by using the linear trapezoidal method. The first order rate constant (λz) of decline in samidorphan plasma concentrations in the terminal phase of the plasma concentration–time curve was estimated by using linear/linear regression. The t½ was estimated from ln2/λz. AUC0–1 was calculated by using the following equation: AUC0–last þ AUCEx, where AUCEx was the observed concentration at last sampling time divided by λz. CL/F was calculated as the dose divided by AUC0–1, and Vd/F was estimated by dividing the apparent CL by λz. For study 2, the PK parameters determined from plasma samidorphan concentration versus time data after single (day 1) and multiple (day 7) administrations were Cmax, Tmax, and AUCτ. For day 7 data only, the following PK parameters were also calculated: AUC0–1, t½, CL/F, and Vd/F (using the same methods described for study 1). The accumulation ratio for samidorphan on day 7 was determined by dividing the AUCτ on day 7 by the AUCτ on day 1.
Safety and Tolerability Assessments Safety evaluations included assessment of AEs, clinically significant abnormal laboratory findings (ie, blood chemistry, hematology, urinalysis), vital signs (heart rate, respiratory rate, seated blood pressure, body temperature [study 2 only], and oxygen saturation [study 2 only]), physical examination findings, and ECG results. AEs included any illness, sign, symptom or clinically significant laboratory findings. For study 1, vital signs were measured at each dosing visit on the morning of admission to the facility and predose and 1, 2, 4, 8, 12, 24, and 36 hours postdose. Physical examinations were conducted at screening, as well as on the morning of admission to the facility for each dosing visit. At the first dosing visit, a 12-lead ECG was obtained on the morning of admission to the facility, then again at predose and at 1, 4, and 24 hours postdose. During the subsequent
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dosing visits, ECGs were obtained predose; at 1, 4, and 24 hours postdose and at the final follow-up visit. A qualified clinician assessed all ECGs. Blood samples for hematology and biochemistry analysis and urine samples for urinalysis were collected at all dosing visits at predose and at 24 hours postdose. For study 2, vital signs were measured at screening, on admission to the facility, and predose and at 1 hour postdose on each dosing day. Serial vital sign measurements were taken on days 1 and 7 at 1, 2, 4, 8, and 12 hours (and at 24 and 36 hours postdose on day 7 only). A final measurement was conducted at the follow-up visit. Body temperature and oxygen saturation measurements were obtained at screening, on admission to the facility, and predose on days 1 through 7. ECGs were conducted during the screening visit, at day –1, predose on days 1 through 7, and at 1 hour postdose on days 1 and 7. An additional assessment at 24 and 36 hours was conducted on day 7 only. Also on day 7, an ECG was repeated at 24 and 36 hours postdose and at the final follow-up visit. A qualified clinician assessed all ECGs. Blood samples for hematology and biochemistry analysis as well as urine samples for urinalysis were collected at screening, day –1, predose on days 2 through 7, at 24 and 36 hours postdose on day 7, and at the follow-up visit.
Statistical Analysis For both studies, the safety analysis population included all subjects who received at least 1 dose of study drug. The PK analysis population included all subjects who received study drug and had at least 1 measurable concentration of samidorphan. Statistical summaries for all PK parameters and dose proportionality analyses were conducted by using SAS version 8.2 (SAS Institute, Inc, Cary, North Carolina) or SAS release 9.1; PK parameters were calculated by using Kinetica 4.4 run on the Windows XP platform (Microsoft Corporation, Redmond, Washington). Samidorphan concentration values that were reported as below the LLOQ (BLOQ) at predose or at time points before the first measurable concentration were reported as zero for PK analyses. Following Cmax, BLOQ values embedded between 2 quantifiable data points were treated as missing. BLOQ values that occurred at the end of the collection interval after the last quantifiable concentration were treated as missing for the purposes of estimating PK parameters and zero
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Clinical Therapeutics for the purpose of descriptive statistics. For study 1, sample size was based on clinical rather than statistical considerations and was expected to provide reasonable point estimates for mean PK parameters. For study 2, preliminary PK data from study 1 were used to calculate sample size. Assuming a 2-fold increase in AUC0–1 and a 1.5-fold increase in Cmax between the 10- and 20-mg dosing groups and a CV of 30%, 12 subjects per dosing group in this study were estimated to provide 490% power to detect the differences in AUC0–1 and Cmax at a 0.05 level of significance (without adjusting for multiplicity) from a 2-group t test with log-transformed PK parameters. PK parameters were summarized by using descriptive statistics (ie, mean [SD], geometric mean [if appropriate], %CV, median, minimum and maximum). For study 1, dose proportionality using AUC0–last, AUC0–1, and Cmax over the administered dose range was determined by using a power model: log (parameter) ¼ a þ b log (dose) where a was the intercept and b was the slope. Dose proportionality was assessed based on whether the 90% CI constructed for the estimate of b was within the interval (0.92–1.08). For study 2, a one-way ANOVA model was used to test dose proportionality, using the logarithmically transformed, dose-normalized AUCτ (or AUC0–t, AUC0–1, or Cmax) as the dependent variable and the categorical variable dose (10 or 20 mg) as the explanatory variable. Dose proportionality was concluded if the 90% CI of the ratio of means for dosenormalized Cmax and AUC fell entirely within the range of 80% to 125%. Repeated measures analysis was conducted on log-transformed Ctrough on day 2 through day 8 (ie, 24 hours’ postdose on day 7) to explore the attainment of steady-state concentrations of samidorphan. Contrasts were tested between a particular time point and the pooled mean over all remaining time points. The first time point on days 1 through 7, which was included in the first nonsignificant contrast, was concluded to be the dosing interval on which steady-state conditions were achieved. Dose proportionality was assessed with linear models on log-transformed, dose-normalized PK parameters (Cmax, AUC0–24, and AUC0–1). The accumulation ratio was estimated by using AUC (day 7:day 1). Safety variables, including treatment-emergent AEs (TEAEs), physical examination findings, ECG
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findings, vital sign measurements, and clinical laboratory test values, were summarized by using descriptive statistics (n, mean [SD], median, minimum and maximum for continuous variables, and counts and frequencies for categorical variables), as well as change from baseline, where applicable. The baseline value was calculated as the first predose value. The incidence of serious AEs and AEs leading to subject discontinuation were also summarized by using descriptive statistics. Descriptive statistics were performed on observed data only.
RESULTS Demographic Characteristics The baseline demographics of study subjects for study 1 and study 2 are summarized in Table I. Sixteen healthy, adult subjects were enrolled in study 1, and the majority were male (93.8%). Their mean age was 29.6 years (range, 18–49 years), and their mean BMI was 26.8 kg/m2 (range, 21.0–29.5 kg/m2). In study 1, the intention was to dose-escalate all subjects across all dose levels, with appropriate
Table I. Baseline demographic characteristics for study 1 and study 2 of samidorphan.
Characteristic
Study 1 (Single-Dose Study)
Sex, no. (%) Male 15 (93.8) Female 1 (6.3) Race, no. (%) White 13 (81.2) Black 3 (18.8) Hispanic 0 Age, y Mean (SD) 29.6 (8.7) Range 18–49 Weight, kg Mean (SD) 84.1 (8.9) Range 67.5–105.1 Body mass index, kg/m2 Mean (SD) 26.8 (2.0) Range 21.0–29.5
Study 2 (Multiple-Dose Study) 24 (80.0) 6 (20.0) 19 (63.3) 8 (26.7) 3 (10.0) 40.1 (8.9) 20–54 78.3 (10.2) 65.3–102.6
25.9 (2.4) 20.7–29.5
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Pharmacokinetics Single-Dose PK Findings After administration of a single oral dose of samidorphan 3.7 mg, the mean plasma samidorphan concentrations were quantifiable for 24 hours and through 36 hours postdose (last time point evaluated) after a single dose of 11, 18.6, 37.2, and 55.7 mg (Figure 1). The concentration–time profiles displayed a dosedependent increase over the entire sampling period. After oral administration, samidorphan was rapidly absorbed, typically attaining Tmax within 1 hour after dosing at all dose levels (Table II). After Cmax was reached, concentrations of samidorphan declined in a monophasic manner for all doses administered, with a t½ of 7 hours for the lowest 4 doses. The mean t½ was slightly higher at 8.3 hours for the highest dose (55.7 mg). The CL/F was moderate ( 60 L/h) and decreased with increasing dose, with a 30% lower mean apparent oral clearance in the 55.7 mg dose group versus the 3.7 mg dose group. The Vd/F was high across all dose levels (600 L). Mean Cmax increased from 7.4 ng/mL at the 3.7 mg dose to 136.5 ng/mL for the 55.7 mg dose, corresponding to approximately an 18-fold increase in Cmax over a 15-fold increase in dose. Dose-normalized mean Cmax values were similar, with considerable overlap in the individual dose-normalized Cmax values over the examined dose range. The mean AUC0–1 and AUC0–last
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Concentration (ng/mL)
A
200
3.7 mg (n = 12) 11 mg (n =10) 18.6 mg (n = 9) 37.2 mg (n = 7) 55.7 mg (n = 7)
150
100
50
0 0
B Concentration (ng/mL)
washout and safety evaluations between dose levels. In addition, over the course of the study, it was intended that each patient serve as his or her own placebo control during 1 randomly assigned visit for the evaluation of safety and tolerability of samidorphan. Nine (56.3%) subjects completed the study, and 7 (43.8%) were discontinued from the study early for withdrawal of consent (2 subjects), AEs (3 subjects), positive urine drug screen results (1 subject), and subject removal from the study (1 subject). Subject discontinuation throughout the duration of the study resulted in decreased sample size at the highest samidorphan dose level. Thirty healthy adults were enrolled in study 2; there were 24 male subjects (80.0%) and 6 female subjects (20.0%). Their mean age was 40.1 years (range, 20–54 years), and their mean BMI was 25.9 kg/m2 (range, 20.7–29.5 kg/m2). Two (6.7%) subjects were discontinued early from the study (1 due to an AE and the other withdrew consent).
4
8
12
16 20 Time (h)
1000
24
28
32
36
3.7 mg (n = 12) 11 mg (n = 10) 18.6 mg (n = 9) 37.2 mg (n = 7) 55.7 mg (n = 7)
100
10
1
0.1 0
4
8
12
16 20 Time (h)
24
28
32
36
Figure 1. Mean (SD) plasma concentration of samidorphan versus time after single oral doses (n indicated in the legend). A, linear scale; B, semi-logarithmic scale.
increased by 21-fold over the 15-fold dose range. The mean dose-normalized samidorphan AUC0–1 and AUC0–last values increased with rising dose level in the tested dose range, indicating greater-than-proportional exposure with dose. This observation was particularly evident with the 37.2 and 55.7 mg doses. Furthermore, the power function regression analysis produced dose proportionality equations, which yielded a slope point estimate and 90% CIs of the following for Cmax, AUC0–last, and AUC0–1: 1.045 (0.9792–1.110), 1.077 (1.019–1.135), and 1.063 (1.006–1.120), respectively. Although point estimates of dose proportionality were 1 for all 3 parameters, dose proportionality for the systemic exposure parameters of samidorphan could not be concluded statistically because the 90% CIs for the slope estimates were not completely contained within the prespecified 0.92 to 1.08 interval.
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Table II. Summary of single-dose pharmacokinetics of samidorphan in healthy volunteers. Unless otherwise indicated, values are given as mean (SD). Dose Level 3.7 mg (n ¼ 12)
Parameter Cmax, ng/mL Tmax, median (range), h t½,h CL/F, L/h Vd/F, L AUC0–last, ng/mL h AUC0–1, ng/mL h Dose normalized Cmax/dose, ng/mL/mg AUC0–1/dose, ng/mL h/mg
7.4 1.0 7.0 63.7 620.9 59.5 64.1
11 mg (n ¼ 10)
(1.7) (1.0–4.0) (1.3) (18.0) (145.3) (24.9) (26.1)
25.2 1.0 7.7 60.5 659.8 187.7 195.2
2.0 (0.5) 17.5 (7.1)
18.6 mg (n ¼ 9)
(6.6) (0.5–2.0) (0.9) (17.7) (171.4) (49.3) (53.7)
2.3 (0.6) 17.7 (4.9)
Multiple-Dose Pharmacokinetics The PK properties of samidorphan after the first dose and 7 daily doses of samidorphan were similar to those observed in the single-dose study (Table III). Samidorphan was rapidly absorbed, with a median Tmax of 1 hour across both study days and dose levels. After achieving peak concentrations, samidorphan plasma levels declined in a monoexponential manner for both dose levels, with a similar t½ for the 10 and 20 mg doses (9.2 and 9.4 hours, respectively). On both study days, Cmax and AUCτ increased with increasing dose. Mean (SD) accumulation ratios were
39.8 1.0 7.9 53.2 594.3 365.0 381.7
37.2 mg (n ¼ 7)
(11.2) (0.5–2.0) (0.9) (17.7) (185.0) (117.3) (128.1)
2.2 (0.6) 20.8 (7.0)
92.3 1.0 7.4 49.6 527.6 747.1 772.9
55.7 mg (n ¼ 7)
(17.2) (0.5–2.0) (0.9) (11.2) (117.3) (165.2) (175.6)
136.5 1.0 8.3 45.3 537.0 1275.0 1340.0
2.5 (0.5) 21.1 (4.8)
(45.2) (1.0–4.0) (1.0) (17.4) (213.7) (372.0) (402.0)
2.5 (0.8) 24.3 (7.3)
low with once-daily administration of either 10 mg (1.63 [0.24]) or 20 mg (1.29 [0.13]) of samidorphan for 7 consecutive days. Trough plasma concentrations are depicted in Figure 2. Repeated measures analyses of log-transformed Ctrough demonstrated that steady-state plasma samidorphan concentrations were approached by day 6 and likely achieved by day 7 of dosing with 10 mg of samidorphan (Table III). Based on ANOVA results alone, steady-state concentrations were not attained for the 20 mg dose of samidorphan (all contrasts, P o 0.05), as Ctrough continued to rise slightly across dosing days.
Table III. Summary of multiple-dose pharmacokinetics of samidorphan in healthy volunteers. Unless otherwise indicated, values are given as mean (SD). Day 1 Parameter Cmax, ng/mL Tmax, median (range), h t½, h CL/F, L/h Vd/F, L AUCτ, ng/mL h AUC0–1, ng/ mL h Accumulation ratio
Day 7
10 mg (n ¼ 12)
20 mg (n ¼ 11)
24.9 (5.9) 1.0 (0.5–2.0) NC NC NC 183 (36) NC NC
50.6 (13.7) 1.0 (0.5–4.0) NC NC NC 379 (74) NC NC
10 mg (n ¼ 12) 39.8 1.0 9.2 35.6 273 303 356 1.63
(10.5) (0.5–4.0) (1.3) (10.1) (69) (89) (115) (0.24)
20 mg (n ¼ 11) 53.8 1.0 9.4 42.2 334 483 571 1.29
(7.9) (0.5–2.0) (1.2) (6.2) (36) (67) (93) (0.13)
NC ¼ not calculated.
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In both studies, TEAEs were mild to moderate in intensity and resolved quickly. The maximum tolerated dose was considered to be the highest dose tested in both studies (55.7 mg for study 1 and 20 mg for study 2). Overall, no clinically relevant changes were noted in clinical laboratory assessments, vital signs, or ECG data.
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DISCUSSION
10 Concentration (ng/mL)
10 mg 20 mg 8 6
0 1
2
3
4
5 6 Time (day)
7
8
9
Figure 2. Mean (SD) samidorphan trough plasma concentrations after multipledose administration.
Evaluation of CIs, however, indicated that steady-state samidorphan concentrations were approached by day 6.
Tolerability Many subjects complained of the bitter taste of this liquid formulation, coded as dysgeusia. For study 1, the most frequent TEAEs were somnolence (60%), nausea (46.7%), and decreased appetite (33.3%) (Table IV). One subject was discontinued prematurely due to recurrent mild elevations of alanine transaminase after both samidorphan and placebo administration. This event was considered by the investigator to be mild in nature and possibly related to study drug; however, upon further investigation, the alanine transaminase elevation was deemed related to weekend construction work conducted by the subject as the elevations were also noted after placebo administration. One subject was discontinued prematurely due to hepatic steatosis, which was considered mild in severity and definitely not related to study drug. One subject discontinued the study prematurely due to cellulitis of the right forearm, considered definitely not related to study drug. For study 2, the most frequent TEAEs were somnolence (66.7%), constipation (36.7%), and nausea (33.3%) (Table IV), and the frequency seemed to be dose related with a greater occurrence at the 20 mg dose of samidorphan. One subject was discontinued prematurely due to an AE of nausea and vomiting after receiving one 10 mg dose of samidorphan; this event was considered by the investigator to be mild in nature and probably related to study drug.
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These 2 studies of samidorphan evaluated the PK parameters and tolerability of single and multiple ascending oral doses in healthy volunteers. The dose levels initially identified for samidorphan reflected the malate salt amount to be dosed in study 1, whereas in study 2, the amount of samidorphan administered was according to the free-base weight. In both studies, samidorphan was rapidly absorbed, with a Tmax of 1 hour, and systemic exposure increased with increases in dose. Samidorphan Cmax values were similar across relevant doses between the 2 studies after the first administration (eg, 25.2 and 24.9 ng/mL after oral administration of 11 and 10 mg in study 1 and study 2, respectively), and variability across Cmax and AUC0–1 values generally ranged from 14% to 33% (%CV). Samidorphan concentrations declined in a monoexponential manner and, after single administration, were measurable at 36 hours across most dose levels. The t½ ranged from 7 to 8 hours across the dose range and was independent of dose after single administration and was slightly longer after repeat administration (9 hours). There was a clear trend toward decreasing samidorphan CL/F with increasing dose. This finding could be due to either changes in clearance or changes in bioavailability with increases in dose. Although samidorphan is primarily metabolized by cytochrome P-450 3A4, it is considered to be a low-affinity substrate (Km, 54 nM; data on file); thus, saturation of the metabolic pathway may not be a plausible explanation for the lack of dose proportionality. The potential for an absorption-related mechanism to be saturated with increasing doses of samidorphan may be explored further; however, the therapeutic dose range of samidorphan is not anticipated to exceed 20 mg. Steady state, as assessed by using log-transformed Ctrough, was approached by day 6 and achieved by day 7 after the 10 mg dose but was not attained for the 20 mg dose. Based on the t½ observed in study 1, the achievement of steady state was anticipated after samidorphan administration on day 3 or day 4 (ie,
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AE Any AE Asthenia Constipation Decreased appetite Diarrhea Dizziness Dry mouth Dysgeusia Fatigue Headache Nausea Somnolence
Study 1
Study 2
Samidorphan Dose
Samidorphan Dose
Placebo (n ¼ 14)
3.7 mg (n ¼ 12)
11 mg (n ¼ 10)
18.6 mg (n ¼ 9)
37.2 mg (n ¼ 7)
55.7 mg (n ¼ 7)
Placebo (n ¼ 6)
10 mg (n ¼ 12)
20 mg (n ¼ 12)
14 (100.0) 0 0 0
12 (100.0) 0 0 0
10 (100.0) 1 (10.0) 0 0
9 (100.0) 0 0 0
7 (100.0) 1 (14.3) 0 3 (42.9)
6 (85.7) 1 (14.3) 0 3 (42.9)
5 (83.3) 0 1 (16.7) 0
12 (100.0) 0 3 (25.0) 0
11 (91.7) 0 7 (58.3) 0
0 0 0 (100.0) (14.3) 0 (21.4) (14.3)
0 0 0 12 (100.0) 1 (8.3) 0 0 0
1 (10.0) 0 0 10 (100.0) 1 (10.0) 0 3 (30.0) 2 (20.0)
0 0 0 9 (100.0) 0 0 0 2 (22.2)
0 0 0 6 (85.7) 1 (14.3) 0 4 (57.1) 6 (85.7)
1 (14.3) 0 0 3 (42.9) 0 0 2 (28.6) 5 (71.4)
0 0 0 0 0 2 (33.3) 1 (16.7) 3 (50.0)
0 2 (16.7) 4 (33.3) 0 0 3 (25.0) 4 (33.3) 9 (75.0)
0 2 (16.7) 1 (8.3) 0 0 2 (16.7) 5 (41.7) 8 (66.7)
14 2 3 2
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346 Table IV. Incidence of adverse events occurring in 410% of subjects in single ascending dose study 1 and multiple-dose study 2. Values are given as number (%) of subjects.
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R. Turncliff et al. 5 half-lives). Interindividual variability of Ctrough was generally higher for the 10-mg dose level (%CV, 34%–50%) than for the 20-mg dose level (%CV, 25%–38%), which may have contributed to the observation of steady-state concentrations by day 7 for the lower dose using the ANOVA model. Samidorphan accumulation was minimal, with accumulation ratios o1.65 across both dose levels. Considering the low accumulation of samidorphan with repeated once-daily dosing and observed intersubject variability of Ctrough, the results of the steady-state analysis may not be clinically meaningful. The apparent discrepancy in the predicted time to steady state based on singledose data compared with the observed multiple-dose time to steady state will be explored in future studies. Samidorphan was generally well tolerated except for dysgeusia related to the bitter taste of the liquid formulation. Somnolence (60.0%–67.7%) and nausea (33.3%–46.7%) were the most commonly reported AEs across both studies. At least 60% of AEs were mild in intensity; there were no severe AEs. In study 1, the incidence of nausea and somnolence was highest at the 37.2 and 55.7 mg doses of samidorphan, suggesting a possible relationship to dose. The AEs observed after samidorphan administration are common in description and frequency to the class of opioid antagonists. After naltrexone administration, somnolence and nausea have been reported in 37% and 34% of patients with alcohol dependence, respectively.17,18 Similarly, a dosedependent increase in the percentage of patients reporting nausea after nalmefene administration (13%–25%) has been described.19 It should be noted, however, that the rate of AEs after samidorphan administration in a small population of healthy volunteers may not be reflective of AEs reported in clinical studies conducted in patients. The safety and tolerability of samidorphan will be explored in the intended treatment population in future studies. Based on the results from the present studies, samidorphan exhibits a PK profile that may offer advantages to other mu opioid antagonists, including oral naltrexone. A study of oral naltrexone in healthy male volunteers reported a half-life of 4 hours and an oral bioavailability of 5% attributed to extensive firstpass hepatic metabolism.20 In the 2 studies reported here, samidorphan demonstrated higher systemic exposure at comparable dose levels and a longer halflife than naltrexone, resulting in measurable concentrations for 424 hours.
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Although the bioavailability of samidorphan has not yet been established in humans, results in animal models predict a bioavailability of 60% to 71%.15 In addition, the affinity of samidorphan for the mu opioid receptor (0.052 nM) is 2 times greater than that of naltrexone (0.11 nM).8 Together, these results suggest the potential for samidorphan to achieve concentrations that result in antagonist activity at lower dose levels relative to naltrexone.
CONCLUSIONS The results from these studies confirm the tolerability profile and potential for once-daily oral dosing with samidorphan. Because these studies did not prespecify that demographic characteristics would be balanced for sex, the studies enrolled primarily male subjects. The inclusion of female subjects in future studies will further the understanding of the tolerability profile of samidorphan. Development of samidorphan is ongoing, including an oral and sublingual tablet form. The potential for samidorphan combined with buprenorphine as a treatment for patients with major depressive disorder and an inadequate response to standard antidepressants is currently under investigation.
ACKNOWLEDGMENTS These studies were funded by Alkermes Inc. The authors thank the following individuals for their contributions to the clinical studies and/or preparation of the manuscript: Ari Illeperuma, Keith Krenz, and Paula Wun of Alkermes, Inc; Philip Leese, MD, Rich Cadmus, MD, and Aniruddha Amrite, PhD, of Quintiles, Inc; Janice Faulknor, MD, Megan Shram, PhD, and Nancy Chen, PhD, of Kendle Early Stage; and Richard Perry, who provided editorial assistance funded by Alkermes, Inc.
CONFLICTS OF INTEREST The authors are employees of Alkermes, Inc. All authors were involved in the design, collection, analysis, and interpretation of data; manuscript review and revision; and the decision to submit the manuscript.
REFERENCES 1. Anton RF. Naltrexone for the management of alcohol dependence. N Engl J Med. 2008;359:715–721. 2. Bart G. Maintenance medication for opiate addiction: the foundation of recovery. J Addict Dis. 2012;31:207–225.
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Clinical Therapeutics 3. Boyer EW. Management of opioid analgesic overdose. N Engl J Med. 2012;367:146–155. 4. Miller PM, Book SW, Stewart SH. Medical treatment of alcohol dependence: a systematic review. Int J Psychiatry Med. 2011;42:227–266. 5. Krupitsky E, Nunes EV, Ling W, et al. Injectable extended-release naltrexone (XR-NTX) for opioid dependence: long-term safety and effectiveness. Addiction. 2013;108:1628–1637. 6. Tetrault JM, Fiellin DA. Current and potential pharmacological treatment options for maintenance therapy in opioid-dependent individuals. Drugs. 2012;72:217–228. 7. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008;11:S133–S153. 8. Wentland MP, Sun X, Bu Y, et al. Part 3: 8-thiocarboxamido and 8-thioforamido derivatives of cyclazocine. Bioorg Med Chem Let. 2005; 15:2547–2551. 9. Wentland MP, Lou R, Lu Q, et al. Synthesis of novel high affinity ligands for opioid receptors. Bioorg Med Chem Let. 2009;19:2289–2294. 10. Todtenkopf MS, Dean RL, Turncliff RZ, et al. In vitro and in vivo characterization of novel opioid antagonists. Alcohol Clin Exp Res. 2008;32: 11A–271A. 11. Cunningham JI, Dean RL, Todtenkopf MS, et al. Samidorphan attenuates drug-induced increases in extracellular dopamine concentrations and drug self-administration in rats. Eur Neuropsychopharmacol. 2014;24(Suppl 2):S489. 12. Eyerman DJ, Dean DL, Todtenkopf MS, et al. Comparison of samidorphan, a novel opioid receptor modulator, and naltrexone on nucleus accumbens dopamine release following ethanol and amphetamine administration. Poster presented at the 40th Annual Meeting of the Society for Neuroscience; November 16, 2010; San Diego, California. Poster 630.7. 13. Todtenkopf MS, O’Neill KS, Kelly SM, et al. The novel opioid
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receptor modulator RDC-0313 (samidorphan) reduces olanzapine induced weight gain in female rats. Poster presented at the 40th Annual Meeting of the Society for Neuroscience; November 16, 2010; San Diego, California. Poster 630.3. 14. Oleson LE, Deaver DR, Turncliff RZ. Inter-species differences in metabolism of ALKS33, a novel opioid receptor modulator. Poster presentation at the FIP Pharmaceutical Sciences 2010 World Congress; November 14-18, 2010; New Orleans, Louisiana. Poster W4299. 15. Oleson LE, Deaver DR, Turncliff RZ. In vitro and in vivo metabolic profiling of samidorphan, a novel opioid receptor modulator. Poster presentation at the FIP Pharmaceutical Sciences 2010 World Congress; November 14–18, 2010; New Orleans, Louisiana. Poster W4319. 16. American Psychiatric Association. Diagnostic and statistical manual
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of mental disorders. 4th Text Revision: DSM-IV-TR. Washington, DC: American Psychiatric Association; 2000. Anton RF, O’Malley SS, Ciraulo DA, et al, COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006;295:2003–2017. Rösner S, Hackl-Herrwerth A, Leucht S, et al. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev. 2010;12:CD001867. Anton RF, Pettinati H, Zweben A, et al. A multi-site dose ranging study of nalmefene in the treatment of alcohol dependence. J Clin Psychopharmacol. 2004;24:421–428. Meyer MC, Straughn AB, Lo MW, et al. Bioequivalence dose-proportionality, and pharmacokinetics of naltrexone after oral administration. J Clin Psychiatry. 1984;45(9 Pt 2): 15–19.
Address correspondence to: Ryan Turncliff, PhD, Alkermes, Inc, 852 Winter Street, Waltham, MA 02451. E-mail: [email protected]
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Original Research
Single- and Multiple-dose Pharmacokinetics of Samidorphan, A Novel Opioid Antagonist, in Healthy Volunteers Ryan Turncliff, PhD; Lauren DiPetrillo, PhD; Bernard Silverman, MD; and Elliot Ehrich, MD Alkermes, Inc, Waltham, Massachusetts ABSTRACT Purpose: Samidorphan (3-carboxamido-4-hydroxy naltrexone) is a novel opioid receptor antagonist that is currently in clinical development. The oral dose pharmacokinetics, safety, and tolerability of samidorphan were evaluated in 2 double-blind, placebo-controlled, randomized studies in healthy adults. Methods: The first study investigated single, ascending doses of 3.7 to 55.7 mg of samidorphan in 16 healthy adults; the second study evaluated multiple ascending doses of 10 or 20 mg of samidorphan administered for 7 days in 30 healthy adults. Findings: Across the two studies, 39 of 46 subjects were male; 32 were white, 11 were black, and 3 were hispanic. Mean age was 34.9 years and mean weight was 84.2 kg. In both studies, samidorphan was rapidly absorbed, with a Tmax of 1 hour, and AUC increased with increasing dose. Samidorphan plasma levels declined in a monoexponential manner, with a half-life of 7 to 9 hours. After multiple doses, steady state was approached by day 6 and achieved by day 7 after the 10-mg dose, but steady state was not reached for the 20-mg dose. Accumulation was low, with accumulation ratios o1.65. In both studies, samidorphan was generally well tolerated, with somnolence reported as the most common adverse event. Implications: In these single- and multiple-dose studies in healthy volunteers, samidorphan exhibited a pharmacokinetic profile consistent with once-daily dosing.ClinicalTrials.gov identifier: NCT00800319. (Clin Ther. 2015;37:338–348) & 2015 Elsevier HS Journals, Inc. All rights reserved. Accepted for publication October 2, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.10.001 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
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Key words: multiple ascending dose trial, opioid receptor antagonist, pharmacokinetics, safety, samidorphan, single ascending dose trial, tolerability.
INTRODUCTION Mu opioid receptor antagonists, such as naltrexone and naloxone, were developed to counteract the negative adverse effects of opioids. Opioid receptor antagonists have demonstrated clinical efficacy for the treatment of alcohol dependence, opioid dependence, and opioid overdose.1–6 However, the pharmacokinetic (PK) properties of oral naltrexone and naloxone have restricted their clinical utility.2–4 Naloxone has a rapid onset of action but low oral bioavailability that limits oral administration. Although this is beneficial for the treatment of opioid overdose, it reduces the benefits of naloxone for the long-term treatment of drug dependence. Similarly, naltrexone has low oral bioavailability due to its high first-pass metabolism.7 Samidorphan (3-carboxamido-4-hydroxy naltrexone) is a novel opioid receptor antagonist with high affinity and functional activity at the mu opioid receptor.8,9 Samidorphan is structurally related to the mixed opioid receptor antagonist naltrexone. In nonclinical rodent studies, oral administration of samidorphan (previously described as RDC-0313 or ALKS 33) reversed morphine-induced analgesia for 44 hours, supporting its ability to block opioid receptors10,11 and significantly reduced alcohol drinking in rats.12 The pharmacodynamic effects of Scan the QR Code with your phone to obtain FREE ACCESS to the articles featured in the Clinical Therapeutics topical updates or text GS2C65 to 64842. To scan QR Codes your phone must have a QR Code reader installed.
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R. Turncliff et al. samidorphan in animal species revealed a profile different from naltrexone.12,13 The in vitro metabolic profile and in vivo PK characteristics of samidorphan in animals were conducive to use as an oral formulation.14,15 After oral administration, samidorphan was rapidly absorbed, with a Tmax of 2 hours. The absolute bioavailability varied across species, with low oral exposure observed in the rat and higher exposure in the dog and monkey. Although the half-life of samidorphan was 2.0 hours in the rat and dog studies,15 in vitro metabolism experiments suggested a prolongation of the half-life of samidorphan in humans.14 After assessment of the safety profile in nonclinical species, the safety and therapeutic potential of samidorphan were assessed in humans. The purpose of the first-in-human study (study 1) was to investigate the acute safety, tolerability, and PK properties of samidorphan after oral administration of single ascending doses of 3.7 to 55.7 mg in healthy adults. The second Phase I study (study 2) investigated the safety, tolerability, and PK properties of samidorphan after daily dosing for 7 days with 10 or 20 mg in healthy adults.
SUBJECTS AND METHODS Each study protocol and the informed consent forms were approved by local ethics committees and institutional review boards, and each subject provided written informed consent before study participation. All subjects were free to withdraw from the study for any reason at any time. Both studies were conducted in compliance with the principles of the Declaration of Helsinki and current International Conference on Harmonisation Guideline for Good Clinical Practice.
Study Subjects In both studies, healthy male and female adults between the ages of 18 and 65 years (study 1) or 18 and 55 years (study 2) with a body mass index (BMI) of Z19.0 kg/m2 and r30.0 kg/m2, with a minimum weight of 50 kg, were eligible. Subjects were required to have no clinically significant medical illness and a normal physical examination, ECG, and clinical laboratory values. All subjects were required to practice an effective method of contraception. Results of urine drug screenings had to be negative both at screening and at admission to the study facility, and a negative hepatitis panel and HIV antibody screen were also required. Subjects with a known allergy or hypersensitivity to opioid antagonists or quinine were excluded. Subjects
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were excluded if they had a history of alcohol or drug dependence (excluding nicotine or caffeine) within the previous 2 years based on criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision.16 Subjects taking chronic medications or likely to require medications during the study were excluded. Subjects also were excluded for use of any prescription or over-the-counter medication, including natural health products (with the exception of prescription contraceptives or hormonal replacements, acetaminophen, ibuprofen, or multivitamins), within 14 days before the first study drug dose; ingestion of alcohol-, caffeine-, or xanthine-containing products within 24 hours before study drug administration; or participation in a clinical trial of a pharmacologic agent within 30 days of screening. Subjects were also excluded if they had donated blood within 60 days of screening.
Study Design Study 1 was a single-center, randomized, doubleblind, placebo-controlled, ascending-dose study. This study consisted of 1 screening visit, 5 dosing visits, and 1 follow-up visit. After successfully completing screening evaluations, 16 consenting, eligible subjects were randomly assigned to 1 of 8 dosing sequences consisting of 5 administrations of an oral solution of either ascending doses of samidorphan (3–4 doses per subject) or volume-matched placebo (1–2 doses per subject). A total of 12 subjects were to receive samidorphan and 4 subjects were to receive placebo at each dose level. As such, each subject served as his or her own placebo control with regard to the safety assessments of samidorphan. A minimum 7-day washout period separated each dosing visit. Dosing of cohorts was staggered to allow a blinded review of safety data (clinical observations and clinical chemistry) to occur before dosing the next cohort; a comprehensive blinded safety review of data obtained for all subjects was conducted before dose escalation. Each dosing visit required a 60-hour inpatient stay. Subjects were admitted to the study facility the morning before each dosing visit and were required to fast overnight before study drug administration. Subjects were discharged from the facility after the 36-hour postdose assessments for each visit were completed. All doses were prepared by an unblinded pharmacist and administered by the blinded study investigator or a designated staff member. Samidorphan doses of 3.7, 11, 18.6, 37.2, and 55.7 mg (equivalent to samidorphan malate salt doses of
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Clinical Therapeutics 5, 15, 25, 50, and 75 mg) were given as a solution of 2 mg/mL and the placebo as a solution of 0.1 g/L quinine sulfate to mask the bitter taste, together with 240 mL of water. Subjects were fasted from 8 hours before until 4 hours after study drug administration, although water ad libitum was allowed. A final follow-up visit occurred 7 days after the last dosing visit. The 3.7-mg starting dose was selected based on the results of safety studies in nonclinical species showing that the highest doses with no observed adverse events (AEs) ranged from 3 to 10 mg/kg (human-equivalent dose of 100 to 300 mg based on a 60-kg human) (data on file). The application of a 10-fold safety factor translated into a maximum safe recommended starting dose for humans of between 10 and 30 mg of samidorphan. The starting dose used in this study, therefore, represented a 41/10th reduction of the dose that did not result in observable AEs (on the basis of body weight) in the most sensitive nonclinical species. Study 2 was a single-center, randomized, doubleblind, placebo-controlled, multiple-dose study. This study consisted of 3 clinic visits, including a screening visit, 1 study drug inpatient dosing visit, and 1 followup visit. After a screening visit, subjects were randomized to receive 7 consecutive daily 10 mg doses of samidorphan or placebo in a 4:1 ratio. After an interim safety review, a second group of subjects were randomized to receive either 20 mg of samidorphan or placebo in the same 4:1 ratio for 7 consecutive days. Subjects remained at the study facility throughout the 9-day dosing and assessment period, beginning on the evening before dose 1 until after the completion of the 36-hour PK sampling time point after dose 7. All doses were prepared by an unblinded pharmacist and administered by the blinded study investigator or a designated staff member. Samidorphan was administered as an oral solution (2 mg/mL in water) at doses of 10 or 20 mg via an oral dosing syringe. Placebo (0.01% quinine sulfate solution, 0.01 g/L) was administered as an oral solution via an oral dosing syringe. Subjects were fasted overnight for at least 10 hours before dosing until 4 hours postdose on day 1 and again on the evening before dose 7. During both of these fasting periods, water was allowed ad libitum until 1 hour predose and otherwise restricted until the end of the fasting period. A total of 200 mL of water was allowed immediately postdose but otherwise was restricted postdose until the end of the fasting period. On days 2 through 6, overnight fasting was not
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required, but dosing occurred before the morning meal. A final follow-up visit occurred 14 days after discharge from the study facility.
Sample Collection For study 1, venous blood samples (4 mL) for samidorphan levels were collected on each dosing day at the following time points: predose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours postdose. For study 2, venous blood samples (4 mL) for samidorphan levels were collected on day 1 at predose and at 0.25, 0.5, 1, 2, 4, 8, and 12 hours postdose. Trough blood samples were collected immediately before dosing on days 2 through 6. On day 7, blood samples were collected at predose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours postdose. A final blood sample was taken at the follow-up visit (approximately day 21). Blood samples were collected into tubes containing potassium EDTA, gently mixed, and stored on ice until sample processing. Plasma was separated by centrifugation (2000 rpm, 15 minutes, 41C) within 60 minutes of sample collection. Plasma samples were stored frozen at –701C until subsequent bioanalytical analysis.
Sample Analysis Plasma was analyzed for samidorphan by using a validated HPLC-MS/MS method with an assay range of 0.25 to 100 ng/mL. Quantification was performed by using quadratic weighted 1/ regression analysis of peak-area response ratio (analyte/internal standard) versus nominal concentration. Calibration standards were prepared fresh daily by using potassium EDTA human plasma matrix. Precision and accuracy were evaluated by analyzing quality control (QC) samples at the lower limit of quantitation (LLOQ; 0.25 ng/mL) and at a low QC (0.75 ng/mL), a mid-QC (12.5 ng/mL), and a high QC (80.2 ng/mL). Precision was expressed as the %CV of each QC concentration. Accuracy was assessed as the proportional difference from the theoretical analyte concentration. Interassay accuracy at the 3 QC levels ranged from 0.8% to 4.6% above the percent theoretical, with the exception of at the LLOQ, which was 12.4%. Interassay precision was r10.0%, except at the LLOQ, which was 13.9%.
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PK Analysis PK analysis was performed according to WinNonlin Professional version 5.2 (Pharsight Corporation, Mountain View, California) by using noncompartmental analysis and actual elapsed time from dosing. The PK parameters determined from plasma samidorphan concentrations versus time data after single-dose administration included Cmax and Tmax, both of which were determined directly from experimental observations. The AUC0–last values were calculated by using the linear trapezoidal method. The first order rate constant (λz) of decline in samidorphan plasma concentrations in the terminal phase of the plasma concentration–time curve was estimated by using linear/linear regression. The t½ was estimated from ln2/λz. AUC0–1 was calculated by using the following equation: AUC0–last þ AUCEx, where AUCEx was the observed concentration at last sampling time divided by λz. CL/F was calculated as the dose divided by AUC0–1, and Vd/F was estimated by dividing the apparent CL by λz. For study 2, the PK parameters determined from plasma samidorphan concentration versus time data after single (day 1) and multiple (day 7) administrations were Cmax, Tmax, and AUCτ. For day 7 data only, the following PK parameters were also calculated: AUC0–1, t½, CL/F, and Vd/F (using the same methods described for study 1). The accumulation ratio for samidorphan on day 7 was determined by dividing the AUCτ on day 7 by the AUCτ on day 1.
Safety and Tolerability Assessments Safety evaluations included assessment of AEs, clinically significant abnormal laboratory findings (ie, blood chemistry, hematology, urinalysis), vital signs (heart rate, respiratory rate, seated blood pressure, body temperature [study 2 only], and oxygen saturation [study 2 only]), physical examination findings, and ECG results. AEs included any illness, sign, symptom or clinically significant laboratory findings. For study 1, vital signs were measured at each dosing visit on the morning of admission to the facility and predose and 1, 2, 4, 8, 12, 24, and 36 hours postdose. Physical examinations were conducted at screening, as well as on the morning of admission to the facility for each dosing visit. At the first dosing visit, a 12-lead ECG was obtained on the morning of admission to the facility, then again at predose and at 1, 4, and 24 hours postdose. During the subsequent
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dosing visits, ECGs were obtained predose; at 1, 4, and 24 hours postdose and at the final follow-up visit. A qualified clinician assessed all ECGs. Blood samples for hematology and biochemistry analysis and urine samples for urinalysis were collected at all dosing visits at predose and at 24 hours postdose. For study 2, vital signs were measured at screening, on admission to the facility, and predose and at 1 hour postdose on each dosing day. Serial vital sign measurements were taken on days 1 and 7 at 1, 2, 4, 8, and 12 hours (and at 24 and 36 hours postdose on day 7 only). A final measurement was conducted at the follow-up visit. Body temperature and oxygen saturation measurements were obtained at screening, on admission to the facility, and predose on days 1 through 7. ECGs were conducted during the screening visit, at day –1, predose on days 1 through 7, and at 1 hour postdose on days 1 and 7. An additional assessment at 24 and 36 hours was conducted on day 7 only. Also on day 7, an ECG was repeated at 24 and 36 hours postdose and at the final follow-up visit. A qualified clinician assessed all ECGs. Blood samples for hematology and biochemistry analysis as well as urine samples for urinalysis were collected at screening, day –1, predose on days 2 through 7, at 24 and 36 hours postdose on day 7, and at the follow-up visit.
Statistical Analysis For both studies, the safety analysis population included all subjects who received at least 1 dose of study drug. The PK analysis population included all subjects who received study drug and had at least 1 measurable concentration of samidorphan. Statistical summaries for all PK parameters and dose proportionality analyses were conducted by using SAS version 8.2 (SAS Institute, Inc, Cary, North Carolina) or SAS release 9.1; PK parameters were calculated by using Kinetica 4.4 run on the Windows XP platform (Microsoft Corporation, Redmond, Washington). Samidorphan concentration values that were reported as below the LLOQ (BLOQ) at predose or at time points before the first measurable concentration were reported as zero for PK analyses. Following Cmax, BLOQ values embedded between 2 quantifiable data points were treated as missing. BLOQ values that occurred at the end of the collection interval after the last quantifiable concentration were treated as missing for the purposes of estimating PK parameters and zero
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Clinical Therapeutics for the purpose of descriptive statistics. For study 1, sample size was based on clinical rather than statistical considerations and was expected to provide reasonable point estimates for mean PK parameters. For study 2, preliminary PK data from study 1 were used to calculate sample size. Assuming a 2-fold increase in AUC0–1 and a 1.5-fold increase in Cmax between the 10- and 20-mg dosing groups and a CV of 30%, 12 subjects per dosing group in this study were estimated to provide 490% power to detect the differences in AUC0–1 and Cmax at a 0.05 level of significance (without adjusting for multiplicity) from a 2-group t test with log-transformed PK parameters. PK parameters were summarized by using descriptive statistics (ie, mean [SD], geometric mean [if appropriate], %CV, median, minimum and maximum). For study 1, dose proportionality using AUC0–last, AUC0–1, and Cmax over the administered dose range was determined by using a power model: log (parameter) ¼ a þ b log (dose) where a was the intercept and b was the slope. Dose proportionality was assessed based on whether the 90% CI constructed for the estimate of b was within the interval (0.92–1.08). For study 2, a one-way ANOVA model was used to test dose proportionality, using the logarithmically transformed, dose-normalized AUCτ (or AUC0–t, AUC0–1, or Cmax) as the dependent variable and the categorical variable dose (10 or 20 mg) as the explanatory variable. Dose proportionality was concluded if the 90% CI of the ratio of means for dosenormalized Cmax and AUC fell entirely within the range of 80% to 125%. Repeated measures analysis was conducted on log-transformed Ctrough on day 2 through day 8 (ie, 24 hours’ postdose on day 7) to explore the attainment of steady-state concentrations of samidorphan. Contrasts were tested between a particular time point and the pooled mean over all remaining time points. The first time point on days 1 through 7, which was included in the first nonsignificant contrast, was concluded to be the dosing interval on which steady-state conditions were achieved. Dose proportionality was assessed with linear models on log-transformed, dose-normalized PK parameters (Cmax, AUC0–24, and AUC0–1). The accumulation ratio was estimated by using AUC (day 7:day 1). Safety variables, including treatment-emergent AEs (TEAEs), physical examination findings, ECG
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findings, vital sign measurements, and clinical laboratory test values, were summarized by using descriptive statistics (n, mean [SD], median, minimum and maximum for continuous variables, and counts and frequencies for categorical variables), as well as change from baseline, where applicable. The baseline value was calculated as the first predose value. The incidence of serious AEs and AEs leading to subject discontinuation were also summarized by using descriptive statistics. Descriptive statistics were performed on observed data only.
RESULTS Demographic Characteristics The baseline demographics of study subjects for study 1 and study 2 are summarized in Table I. Sixteen healthy, adult subjects were enrolled in study 1, and the majority were male (93.8%). Their mean age was 29.6 years (range, 18–49 years), and their mean BMI was 26.8 kg/m2 (range, 21.0–29.5 kg/m2). In study 1, the intention was to dose-escalate all subjects across all dose levels, with appropriate
Table I. Baseline demographic characteristics for study 1 and study 2 of samidorphan.
Characteristic
Study 1 (Single-Dose Study)
Sex, no. (%) Male 15 (93.8) Female 1 (6.3) Race, no. (%) White 13 (81.2) Black 3 (18.8) Hispanic 0 Age, y Mean (SD) 29.6 (8.7) Range 18–49 Weight, kg Mean (SD) 84.1 (8.9) Range 67.5–105.1 Body mass index, kg/m2 Mean (SD) 26.8 (2.0) Range 21.0–29.5
Study 2 (Multiple-Dose Study) 24 (80.0) 6 (20.0) 19 (63.3) 8 (26.7) 3 (10.0) 40.1 (8.9) 20–54 78.3 (10.2) 65.3–102.6
25.9 (2.4) 20.7–29.5
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Pharmacokinetics Single-Dose PK Findings After administration of a single oral dose of samidorphan 3.7 mg, the mean plasma samidorphan concentrations were quantifiable for 24 hours and through 36 hours postdose (last time point evaluated) after a single dose of 11, 18.6, 37.2, and 55.7 mg (Figure 1). The concentration–time profiles displayed a dosedependent increase over the entire sampling period. After oral administration, samidorphan was rapidly absorbed, typically attaining Tmax within 1 hour after dosing at all dose levels (Table II). After Cmax was reached, concentrations of samidorphan declined in a monophasic manner for all doses administered, with a t½ of 7 hours for the lowest 4 doses. The mean t½ was slightly higher at 8.3 hours for the highest dose (55.7 mg). The CL/F was moderate ( 60 L/h) and decreased with increasing dose, with a 30% lower mean apparent oral clearance in the 55.7 mg dose group versus the 3.7 mg dose group. The Vd/F was high across all dose levels (600 L). Mean Cmax increased from 7.4 ng/mL at the 3.7 mg dose to 136.5 ng/mL for the 55.7 mg dose, corresponding to approximately an 18-fold increase in Cmax over a 15-fold increase in dose. Dose-normalized mean Cmax values were similar, with considerable overlap in the individual dose-normalized Cmax values over the examined dose range. The mean AUC0–1 and AUC0–last
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Concentration (ng/mL)
A
200
3.7 mg (n = 12) 11 mg (n =10) 18.6 mg (n = 9) 37.2 mg (n = 7) 55.7 mg (n = 7)
150
100
50
0 0
B Concentration (ng/mL)
washout and safety evaluations between dose levels. In addition, over the course of the study, it was intended that each patient serve as his or her own placebo control during 1 randomly assigned visit for the evaluation of safety and tolerability of samidorphan. Nine (56.3%) subjects completed the study, and 7 (43.8%) were discontinued from the study early for withdrawal of consent (2 subjects), AEs (3 subjects), positive urine drug screen results (1 subject), and subject removal from the study (1 subject). Subject discontinuation throughout the duration of the study resulted in decreased sample size at the highest samidorphan dose level. Thirty healthy adults were enrolled in study 2; there were 24 male subjects (80.0%) and 6 female subjects (20.0%). Their mean age was 40.1 years (range, 20–54 years), and their mean BMI was 25.9 kg/m2 (range, 20.7–29.5 kg/m2). Two (6.7%) subjects were discontinued early from the study (1 due to an AE and the other withdrew consent).
4
8
12
16 20 Time (h)
1000
24
28
32
36
3.7 mg (n = 12) 11 mg (n = 10) 18.6 mg (n = 9) 37.2 mg (n = 7) 55.7 mg (n = 7)
100
10
1
0.1 0
4
8
12
16 20 Time (h)
24
28
32
36
Figure 1. Mean (SD) plasma concentration of samidorphan versus time after single oral doses (n indicated in the legend). A, linear scale; B, semi-logarithmic scale.
increased by 21-fold over the 15-fold dose range. The mean dose-normalized samidorphan AUC0–1 and AUC0–last values increased with rising dose level in the tested dose range, indicating greater-than-proportional exposure with dose. This observation was particularly evident with the 37.2 and 55.7 mg doses. Furthermore, the power function regression analysis produced dose proportionality equations, which yielded a slope point estimate and 90% CIs of the following for Cmax, AUC0–last, and AUC0–1: 1.045 (0.9792–1.110), 1.077 (1.019–1.135), and 1.063 (1.006–1.120), respectively. Although point estimates of dose proportionality were 1 for all 3 parameters, dose proportionality for the systemic exposure parameters of samidorphan could not be concluded statistically because the 90% CIs for the slope estimates were not completely contained within the prespecified 0.92 to 1.08 interval.
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Table II. Summary of single-dose pharmacokinetics of samidorphan in healthy volunteers. Unless otherwise indicated, values are given as mean (SD). Dose Level 3.7 mg (n ¼ 12)
Parameter Cmax, ng/mL Tmax, median (range), h t½,h CL/F, L/h Vd/F, L AUC0–last, ng/mL h AUC0–1, ng/mL h Dose normalized Cmax/dose, ng/mL/mg AUC0–1/dose, ng/mL h/mg
7.4 1.0 7.0 63.7 620.9 59.5 64.1
11 mg (n ¼ 10)
(1.7) (1.0–4.0) (1.3) (18.0) (145.3) (24.9) (26.1)
25.2 1.0 7.7 60.5 659.8 187.7 195.2
2.0 (0.5) 17.5 (7.1)
18.6 mg (n ¼ 9)
(6.6) (0.5–2.0) (0.9) (17.7) (171.4) (49.3) (53.7)
2.3 (0.6) 17.7 (4.9)
Multiple-Dose Pharmacokinetics The PK properties of samidorphan after the first dose and 7 daily doses of samidorphan were similar to those observed in the single-dose study (Table III). Samidorphan was rapidly absorbed, with a median Tmax of 1 hour across both study days and dose levels. After achieving peak concentrations, samidorphan plasma levels declined in a monoexponential manner for both dose levels, with a similar t½ for the 10 and 20 mg doses (9.2 and 9.4 hours, respectively). On both study days, Cmax and AUCτ increased with increasing dose. Mean (SD) accumulation ratios were
39.8 1.0 7.9 53.2 594.3 365.0 381.7
37.2 mg (n ¼ 7)
(11.2) (0.5–2.0) (0.9) (17.7) (185.0) (117.3) (128.1)
2.2 (0.6) 20.8 (7.0)
92.3 1.0 7.4 49.6 527.6 747.1 772.9
55.7 mg (n ¼ 7)
(17.2) (0.5–2.0) (0.9) (11.2) (117.3) (165.2) (175.6)
136.5 1.0 8.3 45.3 537.0 1275.0 1340.0
2.5 (0.5) 21.1 (4.8)
(45.2) (1.0–4.0) (1.0) (17.4) (213.7) (372.0) (402.0)
2.5 (0.8) 24.3 (7.3)
low with once-daily administration of either 10 mg (1.63 [0.24]) or 20 mg (1.29 [0.13]) of samidorphan for 7 consecutive days. Trough plasma concentrations are depicted in Figure 2. Repeated measures analyses of log-transformed Ctrough demonstrated that steady-state plasma samidorphan concentrations were approached by day 6 and likely achieved by day 7 of dosing with 10 mg of samidorphan (Table III). Based on ANOVA results alone, steady-state concentrations were not attained for the 20 mg dose of samidorphan (all contrasts, P o 0.05), as Ctrough continued to rise slightly across dosing days.
Table III. Summary of multiple-dose pharmacokinetics of samidorphan in healthy volunteers. Unless otherwise indicated, values are given as mean (SD). Day 1 Parameter Cmax, ng/mL Tmax, median (range), h t½, h CL/F, L/h Vd/F, L AUCτ, ng/mL h AUC0–1, ng/ mL h Accumulation ratio
Day 7
10 mg (n ¼ 12)
20 mg (n ¼ 11)
24.9 (5.9) 1.0 (0.5–2.0) NC NC NC 183 (36) NC NC
50.6 (13.7) 1.0 (0.5–4.0) NC NC NC 379 (74) NC NC
10 mg (n ¼ 12) 39.8 1.0 9.2 35.6 273 303 356 1.63
(10.5) (0.5–4.0) (1.3) (10.1) (69) (89) (115) (0.24)
20 mg (n ¼ 11) 53.8 1.0 9.4 42.2 334 483 571 1.29
(7.9) (0.5–2.0) (1.2) (6.2) (36) (67) (93) (0.13)
NC ¼ not calculated.
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In both studies, TEAEs were mild to moderate in intensity and resolved quickly. The maximum tolerated dose was considered to be the highest dose tested in both studies (55.7 mg for study 1 and 20 mg for study 2). Overall, no clinically relevant changes were noted in clinical laboratory assessments, vital signs, or ECG data.
2
DISCUSSION
10 Concentration (ng/mL)
10 mg 20 mg 8 6
0 1
2
3
4
5 6 Time (day)
7
8
9
Figure 2. Mean (SD) samidorphan trough plasma concentrations after multipledose administration.
Evaluation of CIs, however, indicated that steady-state samidorphan concentrations were approached by day 6.
Tolerability Many subjects complained of the bitter taste of this liquid formulation, coded as dysgeusia. For study 1, the most frequent TEAEs were somnolence (60%), nausea (46.7%), and decreased appetite (33.3%) (Table IV). One subject was discontinued prematurely due to recurrent mild elevations of alanine transaminase after both samidorphan and placebo administration. This event was considered by the investigator to be mild in nature and possibly related to study drug; however, upon further investigation, the alanine transaminase elevation was deemed related to weekend construction work conducted by the subject as the elevations were also noted after placebo administration. One subject was discontinued prematurely due to hepatic steatosis, which was considered mild in severity and definitely not related to study drug. One subject discontinued the study prematurely due to cellulitis of the right forearm, considered definitely not related to study drug. For study 2, the most frequent TEAEs were somnolence (66.7%), constipation (36.7%), and nausea (33.3%) (Table IV), and the frequency seemed to be dose related with a greater occurrence at the 20 mg dose of samidorphan. One subject was discontinued prematurely due to an AE of nausea and vomiting after receiving one 10 mg dose of samidorphan; this event was considered by the investigator to be mild in nature and probably related to study drug.
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These 2 studies of samidorphan evaluated the PK parameters and tolerability of single and multiple ascending oral doses in healthy volunteers. The dose levels initially identified for samidorphan reflected the malate salt amount to be dosed in study 1, whereas in study 2, the amount of samidorphan administered was according to the free-base weight. In both studies, samidorphan was rapidly absorbed, with a Tmax of 1 hour, and systemic exposure increased with increases in dose. Samidorphan Cmax values were similar across relevant doses between the 2 studies after the first administration (eg, 25.2 and 24.9 ng/mL after oral administration of 11 and 10 mg in study 1 and study 2, respectively), and variability across Cmax and AUC0–1 values generally ranged from 14% to 33% (%CV). Samidorphan concentrations declined in a monoexponential manner and, after single administration, were measurable at 36 hours across most dose levels. The t½ ranged from 7 to 8 hours across the dose range and was independent of dose after single administration and was slightly longer after repeat administration (9 hours). There was a clear trend toward decreasing samidorphan CL/F with increasing dose. This finding could be due to either changes in clearance or changes in bioavailability with increases in dose. Although samidorphan is primarily metabolized by cytochrome P-450 3A4, it is considered to be a low-affinity substrate (Km, 54 nM; data on file); thus, saturation of the metabolic pathway may not be a plausible explanation for the lack of dose proportionality. The potential for an absorption-related mechanism to be saturated with increasing doses of samidorphan may be explored further; however, the therapeutic dose range of samidorphan is not anticipated to exceed 20 mg. Steady state, as assessed by using log-transformed Ctrough, was approached by day 6 and achieved by day 7 after the 10 mg dose but was not attained for the 20 mg dose. Based on the t½ observed in study 1, the achievement of steady state was anticipated after samidorphan administration on day 3 or day 4 (ie,
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AE Any AE Asthenia Constipation Decreased appetite Diarrhea Dizziness Dry mouth Dysgeusia Fatigue Headache Nausea Somnolence
Study 1
Study 2
Samidorphan Dose
Samidorphan Dose
Placebo (n ¼ 14)
3.7 mg (n ¼ 12)
11 mg (n ¼ 10)
18.6 mg (n ¼ 9)
37.2 mg (n ¼ 7)
55.7 mg (n ¼ 7)
Placebo (n ¼ 6)
10 mg (n ¼ 12)
20 mg (n ¼ 12)
14 (100.0) 0 0 0
12 (100.0) 0 0 0
10 (100.0) 1 (10.0) 0 0
9 (100.0) 0 0 0
7 (100.0) 1 (14.3) 0 3 (42.9)
6 (85.7) 1 (14.3) 0 3 (42.9)
5 (83.3) 0 1 (16.7) 0
12 (100.0) 0 3 (25.0) 0
11 (91.7) 0 7 (58.3) 0
0 0 0 (100.0) (14.3) 0 (21.4) (14.3)
0 0 0 12 (100.0) 1 (8.3) 0 0 0
1 (10.0) 0 0 10 (100.0) 1 (10.0) 0 3 (30.0) 2 (20.0)
0 0 0 9 (100.0) 0 0 0 2 (22.2)
0 0 0 6 (85.7) 1 (14.3) 0 4 (57.1) 6 (85.7)
1 (14.3) 0 0 3 (42.9) 0 0 2 (28.6) 5 (71.4)
0 0 0 0 0 2 (33.3) 1 (16.7) 3 (50.0)
0 2 (16.7) 4 (33.3) 0 0 3 (25.0) 4 (33.3) 9 (75.0)
0 2 (16.7) 1 (8.3) 0 0 2 (16.7) 5 (41.7) 8 (66.7)
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346 Table IV. Incidence of adverse events occurring in 410% of subjects in single ascending dose study 1 and multiple-dose study 2. Values are given as number (%) of subjects.
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R. Turncliff et al. 5 half-lives). Interindividual variability of Ctrough was generally higher for the 10-mg dose level (%CV, 34%–50%) than for the 20-mg dose level (%CV, 25%–38%), which may have contributed to the observation of steady-state concentrations by day 7 for the lower dose using the ANOVA model. Samidorphan accumulation was minimal, with accumulation ratios o1.65 across both dose levels. Considering the low accumulation of samidorphan with repeated once-daily dosing and observed intersubject variability of Ctrough, the results of the steady-state analysis may not be clinically meaningful. The apparent discrepancy in the predicted time to steady state based on singledose data compared with the observed multiple-dose time to steady state will be explored in future studies. Samidorphan was generally well tolerated except for dysgeusia related to the bitter taste of the liquid formulation. Somnolence (60.0%–67.7%) and nausea (33.3%–46.7%) were the most commonly reported AEs across both studies. At least 60% of AEs were mild in intensity; there were no severe AEs. In study 1, the incidence of nausea and somnolence was highest at the 37.2 and 55.7 mg doses of samidorphan, suggesting a possible relationship to dose. The AEs observed after samidorphan administration are common in description and frequency to the class of opioid antagonists. After naltrexone administration, somnolence and nausea have been reported in 37% and 34% of patients with alcohol dependence, respectively.17,18 Similarly, a dosedependent increase in the percentage of patients reporting nausea after nalmefene administration (13%–25%) has been described.19 It should be noted, however, that the rate of AEs after samidorphan administration in a small population of healthy volunteers may not be reflective of AEs reported in clinical studies conducted in patients. The safety and tolerability of samidorphan will be explored in the intended treatment population in future studies. Based on the results from the present studies, samidorphan exhibits a PK profile that may offer advantages to other mu opioid antagonists, including oral naltrexone. A study of oral naltrexone in healthy male volunteers reported a half-life of 4 hours and an oral bioavailability of 5% attributed to extensive firstpass hepatic metabolism.20 In the 2 studies reported here, samidorphan demonstrated higher systemic exposure at comparable dose levels and a longer halflife than naltrexone, resulting in measurable concentrations for 424 hours.
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Although the bioavailability of samidorphan has not yet been established in humans, results in animal models predict a bioavailability of 60% to 71%.15 In addition, the affinity of samidorphan for the mu opioid receptor (0.052 nM) is 2 times greater than that of naltrexone (0.11 nM).8 Together, these results suggest the potential for samidorphan to achieve concentrations that result in antagonist activity at lower dose levels relative to naltrexone.
CONCLUSIONS The results from these studies confirm the tolerability profile and potential for once-daily oral dosing with samidorphan. Because these studies did not prespecify that demographic characteristics would be balanced for sex, the studies enrolled primarily male subjects. The inclusion of female subjects in future studies will further the understanding of the tolerability profile of samidorphan. Development of samidorphan is ongoing, including an oral and sublingual tablet form. The potential for samidorphan combined with buprenorphine as a treatment for patients with major depressive disorder and an inadequate response to standard antidepressants is currently under investigation.
ACKNOWLEDGMENTS These studies were funded by Alkermes Inc. The authors thank the following individuals for their contributions to the clinical studies and/or preparation of the manuscript: Ari Illeperuma, Keith Krenz, and Paula Wun of Alkermes, Inc; Philip Leese, MD, Rich Cadmus, MD, and Aniruddha Amrite, PhD, of Quintiles, Inc; Janice Faulknor, MD, Megan Shram, PhD, and Nancy Chen, PhD, of Kendle Early Stage; and Richard Perry, who provided editorial assistance funded by Alkermes, Inc.
CONFLICTS OF INTEREST The authors are employees of Alkermes, Inc. All authors were involved in the design, collection, analysis, and interpretation of data; manuscript review and revision; and the decision to submit the manuscript.
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Clinical Therapeutics 3. Boyer EW. Management of opioid analgesic overdose. N Engl J Med. 2012;367:146–155. 4. Miller PM, Book SW, Stewart SH. Medical treatment of alcohol dependence: a systematic review. Int J Psychiatry Med. 2011;42:227–266. 5. Krupitsky E, Nunes EV, Ling W, et al. Injectable extended-release naltrexone (XR-NTX) for opioid dependence: long-term safety and effectiveness. Addiction. 2013;108:1628–1637. 6. Tetrault JM, Fiellin DA. Current and potential pharmacological treatment options for maintenance therapy in opioid-dependent individuals. Drugs. 2012;72:217–228. 7. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008;11:S133–S153. 8. Wentland MP, Sun X, Bu Y, et al. Part 3: 8-thiocarboxamido and 8-thioforamido derivatives of cyclazocine. Bioorg Med Chem Let. 2005; 15:2547–2551. 9. Wentland MP, Lou R, Lu Q, et al. Synthesis of novel high affinity ligands for opioid receptors. Bioorg Med Chem Let. 2009;19:2289–2294. 10. Todtenkopf MS, Dean RL, Turncliff RZ, et al. In vitro and in vivo characterization of novel opioid antagonists. Alcohol Clin Exp Res. 2008;32: 11A–271A. 11. Cunningham JI, Dean RL, Todtenkopf MS, et al. Samidorphan attenuates drug-induced increases in extracellular dopamine concentrations and drug self-administration in rats. Eur Neuropsychopharmacol. 2014;24(Suppl 2):S489. 12. Eyerman DJ, Dean DL, Todtenkopf MS, et al. Comparison of samidorphan, a novel opioid receptor modulator, and naltrexone on nucleus accumbens dopamine release following ethanol and amphetamine administration. Poster presented at the 40th Annual Meeting of the Society for Neuroscience; November 16, 2010; San Diego, California. Poster 630.7. 13. Todtenkopf MS, O’Neill KS, Kelly SM, et al. The novel opioid
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receptor modulator RDC-0313 (samidorphan) reduces olanzapine induced weight gain in female rats. Poster presented at the 40th Annual Meeting of the Society for Neuroscience; November 16, 2010; San Diego, California. Poster 630.3. 14. Oleson LE, Deaver DR, Turncliff RZ. Inter-species differences in metabolism of ALKS33, a novel opioid receptor modulator. Poster presentation at the FIP Pharmaceutical Sciences 2010 World Congress; November 14-18, 2010; New Orleans, Louisiana. Poster W4299. 15. Oleson LE, Deaver DR, Turncliff RZ. In vitro and in vivo metabolic profiling of samidorphan, a novel opioid receptor modulator. Poster presentation at the FIP Pharmaceutical Sciences 2010 World Congress; November 14–18, 2010; New Orleans, Louisiana. Poster W4319. 16. American Psychiatric Association. Diagnostic and statistical manual
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of mental disorders. 4th Text Revision: DSM-IV-TR. Washington, DC: American Psychiatric Association; 2000. Anton RF, O’Malley SS, Ciraulo DA, et al, COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006;295:2003–2017. Rösner S, Hackl-Herrwerth A, Leucht S, et al. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev. 2010;12:CD001867. Anton RF, Pettinati H, Zweben A, et al. A multi-site dose ranging study of nalmefene in the treatment of alcohol dependence. J Clin Psychopharmacol. 2004;24:421–428. Meyer MC, Straughn AB, Lo MW, et al. Bioequivalence dose-proportionality, and pharmacokinetics of naltrexone after oral administration. J Clin Psychiatry. 1984;45(9 Pt 2): 15–19.
Address correspondence to: Ryan Turncliff, PhD, Alkermes, Inc, 852 Winter Street, Waltham, MA 02451. E-mail: [email protected]
Volume 37 Number 2
