http://informahealthcare.com/xen ISSN: 0049-8254 (print), 1366-5928 (electronic) Xenobiotica, 2015; 45(3): 239–243 ! 2014 Informa UK Ltd. DOI: 10.3109/00498254.2014.960907
RESEARCH ARTICLE
Pharmacokinetics of peramivir after single intravenous doses in healthy Chinese subjects Dan Zhang, Aihua Du, Lina Zhang, Jingyi Ma, Lingjie Meng, Ming Deng, Juan Xu, and Huichen Liu
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Department of Clinical Pharmacology, Aerospace Center Hospital, Haidian District, Beijing, P.R. China
Abstract
Keywords
1. The aim of the study was to evaluate the pharmacokinetics of peramivir after single intravenous (i.v.) doses in healthy Chinese subjects. 2. In a cross-over study, 12 subjects were given 300 and 600 mg peramivir by i.v. infusion. Blood and urine samples were collected at 17 designated time points and 7 designated intervals up to 36 h post-dose. Plasma and urine concentrations of peramivir were quantified by LC-MS/MS. 3. After single i.v. doses of 300 and 600 mg peramivir, Cmax and AUC0–t of peramivir were 21.4 ± 3.7, 41.1 ± 5.3 mgL1 and 55.90 ± 10.62, 112.1 ± 13.2 mgh L1, respectively. Cmax and AUC increased in proportion to the dose. Within 12 h, accumulative urinary recoveries of peramivir after single i.v. doses of 300 and 600 mg peramivir were 84.31 ± 11.75% and 88.10 ± 7.39%, respectively. 4. In healthy Chinese subjects, peramivir displayed linear pharmacokinetics in the range of 300–600 mg, and was primarily excreted via urine as unchanged drug.
Chinese subjects, intravenous infusion, peramivir, pharmacokinetics, plasma, urine
Introduction Pandemic influenza is considered to be one of the most serious potential global public health threats. As neuraminidase inhibitors (NAIs), oral oseltamivir and inhaled zanamivir have been developed and approved for the treatment of acute uncomplicated influenza and influenza prophylaxis for several years, and they are commercially available in many countries and have been used in the events of influenza outbreak and pandemic over the past few years. However, they may be ineffective because some influenza A and B virus variants have shown resistance to them (Gubareva et al., 2001; Kiso et al., 2004), or those formulations provide inadequate drug delivery when they are difficultly used in critically ill patients with severe or life-threatening infections, patients requiring mechanical ventilation, and children patients (Sorbello et al., 2012; Sugaya et al., 2012). Thus, the development of an injectable anti-influenza agent as an alternative to oral oseltamivir and inhaled zanamivir would be particularly important and valuable. Peramivir, (1S,2S,3S,4R)-3-[(1S)-1-acetamido-2-ethylbutyl]-4-(diaminomethylideneamino)-2-hydroxycyclopentane-1carboxylic acid, is a novel and selective NAI developed to treat influenza A and B by acting as a transition-state Address for correspondence: Huichen Liu, Department of Clinical Pharmacology, Aerospace Center Hospital, 15 Yuquan Road, Haidian District, Beijing 100049, P.R. China. Tel: +86-10-59971772. Fax: +8610-59971773. E-mail: [email protected]
History Received 19 July 2014 Revised 29 August 2014 Accepted 29 August 2014 Published online 18 September 2014
analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells (Babu et al., 2000; Bantia et al., 2006; Gubareva et al., 2001). Its chemical structure is shown in Figure 1. It was developed earliest by BioCryst Pharmaceuticals, Inc. (Babu et al., 2000). However, the oral formulation was abandoned because of the lack of significant clinical effects due to its poor bioavailability (Bantia et al., 2006). High plasma level therapy by intravenous (i.v.) administration provides optimal bioavailability, which may result in faster viral clearance. Then, an injectable version has been developed, of which the development is supported by the United States (US) Department of Health and Human Services as a part of the government’s effort to prepare for flu pandemics, including that caused by the highly pathogenic avian influenza virus subtype H5N1. Although i.v. peramivir has been used to treat H1N1 influenza A virus injection under an emergency use authorization (EUA) issued by the US Food and Drug Administration (FDA) since 23 October 2009 (Birnkrant & Cox, 2009; Sorbello et al., 2012; Sugaya et al., 2012), it is still unapproved in the US after the termination of the EUA on 23 June 2010. A phase III trial in 2011 has found the median durations of influenza symptoms were the same with single i.v. injection of peramivir against 5 days of oral oseltamivir for people with seasonal influenza virus infection (Kohno et al., 2011). Meanwhile, Shionogi & Co., Ltd. and Green Cross Corp., which are in partnership with BioCryst, have received marketing and manufacturing authorization for i.v.
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single dose of 600 or 300 mg peramivir. Standardized meals were provided at 0.5 h before and 4, 10 h after dosing. Blood samples were collected by venepuncture into heparinized tubes before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24 and 36 h after dosing. Plasma was separated by centrifugation (3500 g for 5 min at 4 C) and stored immediately at 80 C until analysis. Urine samples were collected in the following intervals: 2–0 h before and 0–2, 2– 4, 4–8, 8–12, 12–24 and 24–36 h after dosing, and the volume of urine collected was recorded. Urine sample aliquots were stored frozen at approximately 80 C until analysis.
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Figure 1. Chemical structure of peramivir.
peramivir under the commercial name RAPIACTAÕ and PeramifluÕ in Japan and Korea, respectively. Peramivir and sodium chloride injection, an injectable peramivir, has also been developed in China. In this study, we have developed a liquid chromatography-tandem mass spectrometric (LC-MS/ MS) method for the quantification of peramivir in human plasma and urine, and evaluated the pharmacokinetics of peramivir in healthy Chinese subjects after single i.v. doses of peramivir and sodium chloride injection containing 300 and 600 mg peramivir.
Materials and methods Study design and subjects The study protocol and informed consent document of a pharmacokinetic study in healthy Chinese subjects after single i.v. doses of peramivir and sodium chloride injection was approved by the Ethics Committee of Aerospace Center Hospital (Beijing, China). This was an open-label, randomized, single-dose, two-treatment, two-period, two-sequence, cross-over study. The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and the law and regulations of the People’s Republic of China. Subject enrolment was planned for up to 12 healthy subjects with half males and half females. All subjects gave informed consent after the aims and risks of the study were fully explained, and then were selected after completing a thorough medical, physical and biochemical examination. Female subjects were to be non-pregnant and of non-childbearing potential (e.g., with the use of accepted methods of contraception). All subjects were required not to take any other medication within 30 days before study entry and during the study, and to abstain from alcohol and tobacco from 48 h before the first dose until the study completion. Drug administration and sample collection Peramivir and sodium chloride injection (containing 300 mg peramivir and 900 mg sodium chloride per 100 mL per packet) was produced by Hebei Tiancheng Pharmaceutical Co., Ltd. (Cangzhou, China), which was authorized by Beijing Haiyan Pharmaceutical Co., Ltd. of Yangtze River Pharmaceutical Group (Beijing, China) for the production. According to the balanced, randomized, cross-over design, each subject received a single dose of 300 or 600 mg peramivir by i.v. drip infusion at a constant rate for 60 min followed by a one-week washout period, and then received a
Safety evaluation Physical examination, vital signs (including resting blood pressure, pulse, temperature, and respiratory rate), clinical laboratory tests (including haematology, urinalysis, blood biochemistry, and blood coagulation test), and 12-lead electrocardiogram (ECG) were conducted on all subjects at the day before the first dose and 48 h after each dose. Chest X-ray was conducted on all subjects, and urine human chorionic gonadotrophin (HCG) test was conducted on female subjects during screening and at study termination. Vital signs were also performed at the day before, 0.5 h before, and 1, 3, 6, 12 and 24 h after each dose. Subjects were monitored throughout the study for adverse events through questions from the clinic staff and were encouraged to report any untoward effects. The severity of each adverse event was determined by the clinic staff based on direct observation and interview with the subject. The investigator judged the relationship of the adverse event to the study treatment. Bioanalysis Peramivir trihydrate (99.6%) and famciclovir (99.9%, internal standard (I.S.)) were purchased from National Institutes for Food and Drug Control (Beijing, China). HPLC grade methanol and acetonitrile were purchased from Thermo Fisher Scientific Inc. (Fair Lawn, NJ). HPLC grade formic acid was purchase from Dikma Technologies Inc. (Lake Forest, CA). Ultrapure water (18.3 Mcm, 25 C) was prepared by deionized water passing through the A-K Lab Pure Water System (Chengdu, China). All other chemicals and solvents were commercially available analytical grade materials used without further purification. Blank (drug free) human plasma and human urine were obtained from healthy volunteers. Plasma and urine concentrations of peramivir were quantified by LC-MS/MS. Frozen plasma samples and urine samples were thawed at ambient temperature, vortex-mixed briefly, and aliquots of 50 mL plasma samples and 15 mL urine samples were prepared by protein precipitation and direct dilution, respectively. Chromatography was carried out on a C18 analytical column (Synergi Hydro-RP 80A, 150 mm 2.0 mm i.d., 4 mm, Phenomenex, Torrance, CA) fitted with an AQ C18 guard column (4.0 mm 2.0 mm i.d., 5mm, Phenomenex, Torrance, CA) under an isocratic elution condition of methanol-0.5% formic acid (35:65, v/v). The flow rate was 0.4 mLmin1 with column temperature maintained at 35 C. Aliquots of 2 mL and 1 mL post-preparative sample solutions were injected onto the column for plasma
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DOI: 10.3109/00498254.2014.960907
and urine concentration analysis, respectively. Hydrophilic impurities were diverted to waste for 1.2 min after injection using a 10-way switching valve, and total run time for each injection was 3.0 min. The mass spectrometer was operated in the electrospray positive ion mode with the MRM transitions at m/z 329.2 ! 100.2 and m/z 329.2 ! 270.2 for peramivir and at m/z 322.1 ! 136.2 for I.S. Other parameters were as follows: Collision gas, curtain gas, gas 1 and gas 2 (all nitrogen) 3, 30, 40 and 45 psi, respectively; dwell time 200 ms; IonSpray voltage 4500 V; source temperature 500 C; declustering potential (DP) 69 V for peramivir and 48 V for I.S.; collision energy (CE) 44 eV (m/z 329.2 ! 100.2) and 23 eV (m/z 329.2 ! 270.2) for peramivir and 38 eV for I.S. Unit resolution was used for both Q1 and Q3 mass detection. The method was fully validated according to European Medicines Agency (EMA) and US FDA guidelines on bioanalytical method validation (EMA, 2011; US FDA, 2001). The retention times for peramivir and I.S. were typically 2.13 and 1.64 min, respectively. No detectable interference was found in any blank plasma and urine samples analyzed. The method was linear in the concentration ranges of 0.0240–60.0 mgL1 for peramivir in plasma, and 0.400– 1000 mgL1 for peramivir in urine. For plasma and urine peramivir concentration analysis, both intra- and inter-batch relative standard deviation (RSD) were less than 8.0% and 4.0%, and relative error (RE) were within ±8.0% and ±10.0% at all quality control (QC) concentrations, respectively. The extraction recoveries were high and reproducible. Co-eluting endogenous substances from plasma and urine did not interfere the measurement of peramivir and I.S. There was no significant decomposition of peramivir under various storage conditions. Pharmacokinetics assessments Main pharmacokinetic parameters (including dose and body weight normalized variables (norm)) were calculated using non-compartmental method derived in WinNonlin 6.3 (Pharsight Corporation, St. Louis, MO). The maximum plasma concentration (Cmax) and the time to reach Cmax (Tmax) were determined from the observed plasma concentrations of peramivir. The area under the plasma concentration-time curve (AUC0–t) was obtained by the linear trapezoidal rule up to the last sampling point with detectable levels. The AUC0–t was extrapolated to infinity (AUC0–1) by adding the quotient of last measurable plasma concentration (Ct) and the terminal elimination rate constant (z). z was determined by linear least squares regression of the terminal portion of the plasma log-transformed concentration-time curve and the corresponding elimination half-life (t1/2) was calculated as 0.693/z. The area under the first moment curve (AUMC) was also calculated by the method of trapezoids. Mean residence time (MRT) was calculated as: MRT0t ¼ AUMC0t =AUC0t , MRT01 ¼ AUMC01 =AUC01 : The apparent clearance (CL) was derived from the ratio dose/AUC0–1. The apparent volume of distribution (Vd) was estimated by the ratio CL/z. The urinary excretion amount (Ae) of peramivir during each interval was calculated by multiplying the urine
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concentration by the volume of urine collected. The accumulative urinary recovery (fe) was calculated by dividing the accumulative urinary excretion amount by dose. Statistical analysis Mean and standard deviation (SD) was calculated for all main pharmacokinetic parameters. The statistical differences in demographics of the subjects between genders were evaluated using one-way analysis of variance (ANOVA) by SAS V9.3 (SAS Institute Inc., Cary, NC). The statistical differences in pharmacokinetic parameters (Tmax excluded) of peramivir between two dose groups were evaluated using mixed effect ANOVA model also by SAS V9.3, with dose, gender, period and sequence as fixed effects, subject (nested within the sequence) as a random effect. P value less than 0.05 was considered statistically significant. Using WinNonlin 6.3, the intra-subject and inter-subject coefficient of variance (CV) for AUC0–t, AUC0–1, and Cmax of peramivir were calculated as follows: Intra-subject CV ¼ 100% ðexpðMSResidualÞ 1Þ0:5 , Inter-subject CV ¼ 100% ðexpðMSSubjectðSeqÞÞ 1Þ0:5 , where MSResidual is Mean Square Residual, and MSSubject(Seq) is Mean Square Subject(Seq) (Health Canada, 2012). Dose proportionality of peramivir was assessed using power model also by SAS V9.3. The relationship between the pharmacokinetic parameter (y) and dose was defined as y ¼ dose (Gough et al., 1995). Approximate dose proportionality was concluded if the 90% confidence interval (CI) around of Cmax, AUC0–t and AUC0–1 values were entirely within lnðL Þ lnðU Þ ,1 þ 1þ lnðr Þ lnðr Þ where (L, U) was the pre-defined equivalence criterion, r was the ratio of the highest to the lowest dose (Smith et al., 2000), which was 2 in this study. Given the pre-specified equivalence criterion of (0.8000, 1.2500), the calculated limit for 90% CI around would be (0.6781, 1.3219).
Results and discussion Subjects and tolerability A total of 12 healthy subjects (6 males, and 6 females) were recruited and completed the study. The demographic characteristics of subjects are summarized in Table 1. Female subjects represented lower body weight and height compared with male subjects, while no significant differences in age and body mass index (BMI) were found between genders. During the study, 4 (2 males, and 2 females) of 12 subjects reported a total of 6 adverse events (AEs), all of which were mild in severity and resolved by study completion. The AEs included hemoglobin reduction (2 subjects), lymphopenia (1 subject), fibrinogen reduction (1 subject) and thrombin time prolonging (2 subjects). All the AEs were considered as probably not treatment-related. There were no clinically significant findings in the physical examination, vital signs, urinalysis, blood biochemistry, 12-lead ECG or chest X-ray.
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Table 1. Demographic characteristics of subjects. Demographic characteristics Age (y) Body weight (kg)a Body height (m)a BMI (kgm2)
All subjects (n ¼ 12)
Male subjects (n ¼ 6)
Female subject (n ¼ 6)
27 ± 6 (21–38) 60.8 ± 6.3 (50.2–71.3) 1.68 ± 0.06 (1.57–1.80) 21.5 ± 1.4 (18.6–23.1)
26 ± 4 (21–31) 64.6 ± 3.5 (62.2–71.3) 1.72 ± 0.05 (1.67–1.80) 22.0 ± 0.6 (20.9–22.4)
27 ± 8 (21–38) 57.1 ± 6.5 (50.2–67.5) 1.65 ± 0.05 (1.57–1.71) 21.1 ± 1.9 (18.6–23.1)
Data are shown as mean ± SD (range). a Significantly different between two genders (p50.05).
Table 2. Main pharmacokinetic parameters of peramivir in healthy Chinese subjects after single i.v. doses of 300 and 600 mg peramivir. Dose (mg) Parameters
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1 a,b
Figure 2. Mean plasma concentration–time profiles of peramivir in healthy Chinese subjects after single i.v. doses of 300 and 600 mg peramivir. Data are shown as mean + SD (n ¼ 12).
Cmax (mgL ) AUC0–t (mgh L1)a AUC0–1 (mgh L1)a Cmax norm AUC0–t norm AUC0–1 norm t1/2 (h) CL (L h1) CL (L h1 kg1) Vd (L) Vd (L kg1) MRT0–t (h) MRT0–1 (h) Ae 0–36 h (mg)a fe 0–36 h (%)
300
600
21.4 ± 3.7 55.90 ± 10.62 56.13 ± 10.64 4.30 ± 0.53 11.22 ± 1.90 11.26 ± 1.90 2.60 ± 0.61 5.52 ± 1.05 0.0907 ± 0.0124 20.11 ± 2.95 0.333 ± 0.055 2.37 ± 0.34 2.45 ± 0.35 259.94 ± 36.08 86.65 ± 12.03
41.1 ± 5.3 112.1 ± 13.2 112.3 ± 13.2 4.14 ± 0.47 11.28 ± 1.03 11.30 ± 1.03 3.28 ± 1.15 5.41 ± 0.69 0.0892 ± 0.0088 25.17 ± 7.21 0.420 ± 0.146 2.57 ± 0.39 2.62 ± 0.39 543.92 ± 44.43 90.65 ± 7.41
Data are shown as mean ± SD, n ¼ 12. norm, Normalized for dose and body weight (mg kg1). a Significantly different between two doses (p50.05). b Significantly different between two genders (p50.05).
Figure 3. Mean accumulative urinary recovery–time profiles of peramivir in healthy Chinese subjects after single i.v. doses of 300 and 600 mg peramivir. Data are shown as mean + SD (n ¼ 12).
Overall, peramivir was generally well tolerated in healthy Chinese subjects following single i.v. doses of 300 and 600 mg peramivir. Pharmacokinetics Mean plasma concentration–time profiles and mean accumulative urinary recovery-time profiles of peramivir in healthy Chinese subjects after single i.v. doses of 300 and 600 mg peramivir are displayed in Figures 2 and 3, respectively, with the main pharmacokinetic parameters, and the urinary
excretion amount and the accumulative urinary recovery within 36 h summarized in Table 2. No significant differences in the pharmacokinetic parameters of peramivir except Cmax were found between genders. Cmax of peramivir in female and male subjects after single i.v. dose of 300 mg peramivir were 23.3 ± 4.4 and 19.6 ± 1.7 mgL1, and were 43.4 ± 5.5 and 38.9 ± 4.4 mgL1 after single i.v. dose of 600 mg peramivir, respectively. Female subjects represented higher Cmax compared with male subjects. This might result from the significant differences in body weight between genders. After correction for body weight, there was no gender-related significant difference in Cmax of peramivir. In addition, the intra-subject and inter-subject CV for AUC0–t, AUC0–1, and Cmax of peramivir were 7.1% and 11.7%, 7.1% and 11.6%, and 13.5% and 6.2%, respectively. The results indicated that i.v. peramivir was not a highly variable drug. Between two doses, the Cmax, AUC0–t, and AUC0–1 values of peramivir were significantly different, while no significant differences were found in t1/2, CL and Vd values. Meanwhile, after normalizing for dose and body weight (mgkg1), there was no significant difference in Cmax, AUC0–t, and AUC0–1 of peramivir between two doses. After single i.v. doses of 300 and 600 mg peramivir, of Cmax, AUC0–t and AUC0–1 values were 0.9480, 1.0184, and 1.0151, respectively. The 90% CI
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DOI: 10.3109/00498254.2014.960907
around of Cmax, AUC0–t and AUC0–1 values were 0.8046– 1.0913, 0.9432–1.0937, and 0.9396–1.0906, respectively, which entirely within the limit of (0.6781, 1.3219). Thus, the dose proportionality of peramivir in healthy Chinese subjects after single i.v. doses in the range of 300–600 mg could be concluded. Within 2, 4, 8, 12 and 36 h, accumulative urinary recoveries of peramivir after single i.v. doses of 300 mg peramivir were 41.60 ± 9.37%, 61.45 ± 13.83%, 79.86 ± 11.57%, 84.31 ± 11.75% and 86.51 ± 12.02%, and those after single i.v. dose of 600 mg peramivir were 43.45 ± 4.94%, 64.18 ± 7.30%, 82.79 ± 8.56%, 88.10 ± 7.39% and 90.50 ± 7.38%, respectively. There was no significant difference in the urinary recovery of peramivir between two doses and between two genders. The majority of the administrated dose was excreted in urine as unchanged drug, indicating that renal clearance was the primary elimination route of peramivir. Moreover, the CL value of peramivir was similar with creatinine clearance rate (Ccr) in normal adults. Thus, the systemic exposures of peramivir in patients with renal impairment would be expected to be higher than those in patients with normal renal function, and individualized dose regimen of peramivir and sodium chloride injection based on Ccr would be beneficial for the rational usage of the drug in renally impaired patients (Swan et al., 2009). The mean systemic exposures in patients with mild (50 mLmin1 Ccr580 mLmin1), moderate (30 mLmin1 Ccr550 mLmin1), and sever (10 mLmin1 Ccr530 mLmin1) renal impairment were about 24%, 3.4-fold, and 6-fold higher than those in patients with normal renal function, respectively (PMDA, 2013; US FDA, 2009). Therefore, no dose adjustments of peramivir were needed for the patients with mild renal impairment, and the doses of peramivir for the patients with moderate and sever renal impairment should be reduced to a quarter and one sixth of the dose used in the patients with normal renal function, respectively (PMDA, 2013; US FDA, 2009). Moreover, there was no gender-related significant difference in the main pharmacokinetic parameters and accumulative urinary recoveries of peramivir observed after single i.v. doses of 300 and 600 mg peramivir in this study, the intrasubject and inter-subject CV for AUC0–t, AUC0–1, and Cmax of peramivir were all lower than 15.0%, and the pharmacokinetic data compared well with those reported in the fact sheet of i.v. peramivir (US FDA, 2009) and in the label of RAPIACTAÕ (PMDA, 2013). Compared to primarily metabolically cleared drugs, where enzyme polymorphisms had varying frequencies, i.v. peramivir as a primarily renally cleared drug showed similar pharmacokinetic characteristic in different ethnics groups, and different genders with the similar renal function. Thus, there might be no need to conduct extensive pharmacokinetics evaluation of i.v. peramivir between different ethnics groups and between different genders, and this could speed up the universal adoption of emergency drugs such as i.v. peramivir.
Conclusion In this study, the pharmacokinetics of peramivir in healthy Chinese subjects after single i.v. doses of 300 and 600 mg
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peramivir were evaluated. In healthy Chinese subjects, peramivir was generally well tolerated, displayed linear pharmacokinetics in the range of 300–600 mg, and was primarily excreted via urine as unchanged drug.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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RESEARCH ARTICLE
Pharmacokinetics of peramivir after single intravenous doses in healthy Chinese subjects Dan Zhang, Aihua Du, Lina Zhang, Jingyi Ma, Lingjie Meng, Ming Deng, Juan Xu, and Huichen Liu
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Department of Clinical Pharmacology, Aerospace Center Hospital, Haidian District, Beijing, P.R. China
Abstract
Keywords
1. The aim of the study was to evaluate the pharmacokinetics of peramivir after single intravenous (i.v.) doses in healthy Chinese subjects. 2. In a cross-over study, 12 subjects were given 300 and 600 mg peramivir by i.v. infusion. Blood and urine samples were collected at 17 designated time points and 7 designated intervals up to 36 h post-dose. Plasma and urine concentrations of peramivir were quantified by LC-MS/MS. 3. After single i.v. doses of 300 and 600 mg peramivir, Cmax and AUC0–t of peramivir were 21.4 ± 3.7, 41.1 ± 5.3 mgL1 and 55.90 ± 10.62, 112.1 ± 13.2 mgh L1, respectively. Cmax and AUC increased in proportion to the dose. Within 12 h, accumulative urinary recoveries of peramivir after single i.v. doses of 300 and 600 mg peramivir were 84.31 ± 11.75% and 88.10 ± 7.39%, respectively. 4. In healthy Chinese subjects, peramivir displayed linear pharmacokinetics in the range of 300–600 mg, and was primarily excreted via urine as unchanged drug.
Chinese subjects, intravenous infusion, peramivir, pharmacokinetics, plasma, urine
Introduction Pandemic influenza is considered to be one of the most serious potential global public health threats. As neuraminidase inhibitors (NAIs), oral oseltamivir and inhaled zanamivir have been developed and approved for the treatment of acute uncomplicated influenza and influenza prophylaxis for several years, and they are commercially available in many countries and have been used in the events of influenza outbreak and pandemic over the past few years. However, they may be ineffective because some influenza A and B virus variants have shown resistance to them (Gubareva et al., 2001; Kiso et al., 2004), or those formulations provide inadequate drug delivery when they are difficultly used in critically ill patients with severe or life-threatening infections, patients requiring mechanical ventilation, and children patients (Sorbello et al., 2012; Sugaya et al., 2012). Thus, the development of an injectable anti-influenza agent as an alternative to oral oseltamivir and inhaled zanamivir would be particularly important and valuable. Peramivir, (1S,2S,3S,4R)-3-[(1S)-1-acetamido-2-ethylbutyl]-4-(diaminomethylideneamino)-2-hydroxycyclopentane-1carboxylic acid, is a novel and selective NAI developed to treat influenza A and B by acting as a transition-state Address for correspondence: Huichen Liu, Department of Clinical Pharmacology, Aerospace Center Hospital, 15 Yuquan Road, Haidian District, Beijing 100049, P.R. China. Tel: +86-10-59971772. Fax: +8610-59971773. E-mail: [email protected]
History Received 19 July 2014 Revised 29 August 2014 Accepted 29 August 2014 Published online 18 September 2014
analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells (Babu et al., 2000; Bantia et al., 2006; Gubareva et al., 2001). Its chemical structure is shown in Figure 1. It was developed earliest by BioCryst Pharmaceuticals, Inc. (Babu et al., 2000). However, the oral formulation was abandoned because of the lack of significant clinical effects due to its poor bioavailability (Bantia et al., 2006). High plasma level therapy by intravenous (i.v.) administration provides optimal bioavailability, which may result in faster viral clearance. Then, an injectable version has been developed, of which the development is supported by the United States (US) Department of Health and Human Services as a part of the government’s effort to prepare for flu pandemics, including that caused by the highly pathogenic avian influenza virus subtype H5N1. Although i.v. peramivir has been used to treat H1N1 influenza A virus injection under an emergency use authorization (EUA) issued by the US Food and Drug Administration (FDA) since 23 October 2009 (Birnkrant & Cox, 2009; Sorbello et al., 2012; Sugaya et al., 2012), it is still unapproved in the US after the termination of the EUA on 23 June 2010. A phase III trial in 2011 has found the median durations of influenza symptoms were the same with single i.v. injection of peramivir against 5 days of oral oseltamivir for people with seasonal influenza virus infection (Kohno et al., 2011). Meanwhile, Shionogi & Co., Ltd. and Green Cross Corp., which are in partnership with BioCryst, have received marketing and manufacturing authorization for i.v.
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single dose of 600 or 300 mg peramivir. Standardized meals were provided at 0.5 h before and 4, 10 h after dosing. Blood samples were collected by venepuncture into heparinized tubes before and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24 and 36 h after dosing. Plasma was separated by centrifugation (3500 g for 5 min at 4 C) and stored immediately at 80 C until analysis. Urine samples were collected in the following intervals: 2–0 h before and 0–2, 2– 4, 4–8, 8–12, 12–24 and 24–36 h after dosing, and the volume of urine collected was recorded. Urine sample aliquots were stored frozen at approximately 80 C until analysis.
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Figure 1. Chemical structure of peramivir.
peramivir under the commercial name RAPIACTAÕ and PeramifluÕ in Japan and Korea, respectively. Peramivir and sodium chloride injection, an injectable peramivir, has also been developed in China. In this study, we have developed a liquid chromatography-tandem mass spectrometric (LC-MS/ MS) method for the quantification of peramivir in human plasma and urine, and evaluated the pharmacokinetics of peramivir in healthy Chinese subjects after single i.v. doses of peramivir and sodium chloride injection containing 300 and 600 mg peramivir.
Materials and methods Study design and subjects The study protocol and informed consent document of a pharmacokinetic study in healthy Chinese subjects after single i.v. doses of peramivir and sodium chloride injection was approved by the Ethics Committee of Aerospace Center Hospital (Beijing, China). This was an open-label, randomized, single-dose, two-treatment, two-period, two-sequence, cross-over study. The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and the law and regulations of the People’s Republic of China. Subject enrolment was planned for up to 12 healthy subjects with half males and half females. All subjects gave informed consent after the aims and risks of the study were fully explained, and then were selected after completing a thorough medical, physical and biochemical examination. Female subjects were to be non-pregnant and of non-childbearing potential (e.g., with the use of accepted methods of contraception). All subjects were required not to take any other medication within 30 days before study entry and during the study, and to abstain from alcohol and tobacco from 48 h before the first dose until the study completion. Drug administration and sample collection Peramivir and sodium chloride injection (containing 300 mg peramivir and 900 mg sodium chloride per 100 mL per packet) was produced by Hebei Tiancheng Pharmaceutical Co., Ltd. (Cangzhou, China), which was authorized by Beijing Haiyan Pharmaceutical Co., Ltd. of Yangtze River Pharmaceutical Group (Beijing, China) for the production. According to the balanced, randomized, cross-over design, each subject received a single dose of 300 or 600 mg peramivir by i.v. drip infusion at a constant rate for 60 min followed by a one-week washout period, and then received a
Safety evaluation Physical examination, vital signs (including resting blood pressure, pulse, temperature, and respiratory rate), clinical laboratory tests (including haematology, urinalysis, blood biochemistry, and blood coagulation test), and 12-lead electrocardiogram (ECG) were conducted on all subjects at the day before the first dose and 48 h after each dose. Chest X-ray was conducted on all subjects, and urine human chorionic gonadotrophin (HCG) test was conducted on female subjects during screening and at study termination. Vital signs were also performed at the day before, 0.5 h before, and 1, 3, 6, 12 and 24 h after each dose. Subjects were monitored throughout the study for adverse events through questions from the clinic staff and were encouraged to report any untoward effects. The severity of each adverse event was determined by the clinic staff based on direct observation and interview with the subject. The investigator judged the relationship of the adverse event to the study treatment. Bioanalysis Peramivir trihydrate (99.6%) and famciclovir (99.9%, internal standard (I.S.)) were purchased from National Institutes for Food and Drug Control (Beijing, China). HPLC grade methanol and acetonitrile were purchased from Thermo Fisher Scientific Inc. (Fair Lawn, NJ). HPLC grade formic acid was purchase from Dikma Technologies Inc. (Lake Forest, CA). Ultrapure water (18.3 Mcm, 25 C) was prepared by deionized water passing through the A-K Lab Pure Water System (Chengdu, China). All other chemicals and solvents were commercially available analytical grade materials used without further purification. Blank (drug free) human plasma and human urine were obtained from healthy volunteers. Plasma and urine concentrations of peramivir were quantified by LC-MS/MS. Frozen plasma samples and urine samples were thawed at ambient temperature, vortex-mixed briefly, and aliquots of 50 mL plasma samples and 15 mL urine samples were prepared by protein precipitation and direct dilution, respectively. Chromatography was carried out on a C18 analytical column (Synergi Hydro-RP 80A, 150 mm 2.0 mm i.d., 4 mm, Phenomenex, Torrance, CA) fitted with an AQ C18 guard column (4.0 mm 2.0 mm i.d., 5mm, Phenomenex, Torrance, CA) under an isocratic elution condition of methanol-0.5% formic acid (35:65, v/v). The flow rate was 0.4 mLmin1 with column temperature maintained at 35 C. Aliquots of 2 mL and 1 mL post-preparative sample solutions were injected onto the column for plasma
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DOI: 10.3109/00498254.2014.960907
and urine concentration analysis, respectively. Hydrophilic impurities were diverted to waste for 1.2 min after injection using a 10-way switching valve, and total run time for each injection was 3.0 min. The mass spectrometer was operated in the electrospray positive ion mode with the MRM transitions at m/z 329.2 ! 100.2 and m/z 329.2 ! 270.2 for peramivir and at m/z 322.1 ! 136.2 for I.S. Other parameters were as follows: Collision gas, curtain gas, gas 1 and gas 2 (all nitrogen) 3, 30, 40 and 45 psi, respectively; dwell time 200 ms; IonSpray voltage 4500 V; source temperature 500 C; declustering potential (DP) 69 V for peramivir and 48 V for I.S.; collision energy (CE) 44 eV (m/z 329.2 ! 100.2) and 23 eV (m/z 329.2 ! 270.2) for peramivir and 38 eV for I.S. Unit resolution was used for both Q1 and Q3 mass detection. The method was fully validated according to European Medicines Agency (EMA) and US FDA guidelines on bioanalytical method validation (EMA, 2011; US FDA, 2001). The retention times for peramivir and I.S. were typically 2.13 and 1.64 min, respectively. No detectable interference was found in any blank plasma and urine samples analyzed. The method was linear in the concentration ranges of 0.0240–60.0 mgL1 for peramivir in plasma, and 0.400– 1000 mgL1 for peramivir in urine. For plasma and urine peramivir concentration analysis, both intra- and inter-batch relative standard deviation (RSD) were less than 8.0% and 4.0%, and relative error (RE) were within ±8.0% and ±10.0% at all quality control (QC) concentrations, respectively. The extraction recoveries were high and reproducible. Co-eluting endogenous substances from plasma and urine did not interfere the measurement of peramivir and I.S. There was no significant decomposition of peramivir under various storage conditions. Pharmacokinetics assessments Main pharmacokinetic parameters (including dose and body weight normalized variables (norm)) were calculated using non-compartmental method derived in WinNonlin 6.3 (Pharsight Corporation, St. Louis, MO). The maximum plasma concentration (Cmax) and the time to reach Cmax (Tmax) were determined from the observed plasma concentrations of peramivir. The area under the plasma concentration-time curve (AUC0–t) was obtained by the linear trapezoidal rule up to the last sampling point with detectable levels. The AUC0–t was extrapolated to infinity (AUC0–1) by adding the quotient of last measurable plasma concentration (Ct) and the terminal elimination rate constant (z). z was determined by linear least squares regression of the terminal portion of the plasma log-transformed concentration-time curve and the corresponding elimination half-life (t1/2) was calculated as 0.693/z. The area under the first moment curve (AUMC) was also calculated by the method of trapezoids. Mean residence time (MRT) was calculated as: MRT0t ¼ AUMC0t =AUC0t , MRT01 ¼ AUMC01 =AUC01 : The apparent clearance (CL) was derived from the ratio dose/AUC0–1. The apparent volume of distribution (Vd) was estimated by the ratio CL/z. The urinary excretion amount (Ae) of peramivir during each interval was calculated by multiplying the urine
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concentration by the volume of urine collected. The accumulative urinary recovery (fe) was calculated by dividing the accumulative urinary excretion amount by dose. Statistical analysis Mean and standard deviation (SD) was calculated for all main pharmacokinetic parameters. The statistical differences in demographics of the subjects between genders were evaluated using one-way analysis of variance (ANOVA) by SAS V9.3 (SAS Institute Inc., Cary, NC). The statistical differences in pharmacokinetic parameters (Tmax excluded) of peramivir between two dose groups were evaluated using mixed effect ANOVA model also by SAS V9.3, with dose, gender, period and sequence as fixed effects, subject (nested within the sequence) as a random effect. P value less than 0.05 was considered statistically significant. Using WinNonlin 6.3, the intra-subject and inter-subject coefficient of variance (CV) for AUC0–t, AUC0–1, and Cmax of peramivir were calculated as follows: Intra-subject CV ¼ 100% ðexpðMSResidualÞ 1Þ0:5 , Inter-subject CV ¼ 100% ðexpðMSSubjectðSeqÞÞ 1Þ0:5 , where MSResidual is Mean Square Residual, and MSSubject(Seq) is Mean Square Subject(Seq) (Health Canada, 2012). Dose proportionality of peramivir was assessed using power model also by SAS V9.3. The relationship between the pharmacokinetic parameter (y) and dose was defined as y ¼ dose (Gough et al., 1995). Approximate dose proportionality was concluded if the 90% confidence interval (CI) around of Cmax, AUC0–t and AUC0–1 values were entirely within lnðL Þ lnðU Þ ,1 þ 1þ lnðr Þ lnðr Þ where (L, U) was the pre-defined equivalence criterion, r was the ratio of the highest to the lowest dose (Smith et al., 2000), which was 2 in this study. Given the pre-specified equivalence criterion of (0.8000, 1.2500), the calculated limit for 90% CI around would be (0.6781, 1.3219).
Results and discussion Subjects and tolerability A total of 12 healthy subjects (6 males, and 6 females) were recruited and completed the study. The demographic characteristics of subjects are summarized in Table 1. Female subjects represented lower body weight and height compared with male subjects, while no significant differences in age and body mass index (BMI) were found between genders. During the study, 4 (2 males, and 2 females) of 12 subjects reported a total of 6 adverse events (AEs), all of which were mild in severity and resolved by study completion. The AEs included hemoglobin reduction (2 subjects), lymphopenia (1 subject), fibrinogen reduction (1 subject) and thrombin time prolonging (2 subjects). All the AEs were considered as probably not treatment-related. There were no clinically significant findings in the physical examination, vital signs, urinalysis, blood biochemistry, 12-lead ECG or chest X-ray.
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Table 1. Demographic characteristics of subjects. Demographic characteristics Age (y) Body weight (kg)a Body height (m)a BMI (kgm2)
All subjects (n ¼ 12)
Male subjects (n ¼ 6)
Female subject (n ¼ 6)
27 ± 6 (21–38) 60.8 ± 6.3 (50.2–71.3) 1.68 ± 0.06 (1.57–1.80) 21.5 ± 1.4 (18.6–23.1)
26 ± 4 (21–31) 64.6 ± 3.5 (62.2–71.3) 1.72 ± 0.05 (1.67–1.80) 22.0 ± 0.6 (20.9–22.4)
27 ± 8 (21–38) 57.1 ± 6.5 (50.2–67.5) 1.65 ± 0.05 (1.57–1.71) 21.1 ± 1.9 (18.6–23.1)
Data are shown as mean ± SD (range). a Significantly different between two genders (p50.05).
Table 2. Main pharmacokinetic parameters of peramivir in healthy Chinese subjects after single i.v. doses of 300 and 600 mg peramivir. Dose (mg) Parameters
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1 a,b
Figure 2. Mean plasma concentration–time profiles of peramivir in healthy Chinese subjects after single i.v. doses of 300 and 600 mg peramivir. Data are shown as mean + SD (n ¼ 12).
Cmax (mgL ) AUC0–t (mgh L1)a AUC0–1 (mgh L1)a Cmax norm AUC0–t norm AUC0–1 norm t1/2 (h) CL (L h1) CL (L h1 kg1) Vd (L) Vd (L kg1) MRT0–t (h) MRT0–1 (h) Ae 0–36 h (mg)a fe 0–36 h (%)
300
600
21.4 ± 3.7 55.90 ± 10.62 56.13 ± 10.64 4.30 ± 0.53 11.22 ± 1.90 11.26 ± 1.90 2.60 ± 0.61 5.52 ± 1.05 0.0907 ± 0.0124 20.11 ± 2.95 0.333 ± 0.055 2.37 ± 0.34 2.45 ± 0.35 259.94 ± 36.08 86.65 ± 12.03
41.1 ± 5.3 112.1 ± 13.2 112.3 ± 13.2 4.14 ± 0.47 11.28 ± 1.03 11.30 ± 1.03 3.28 ± 1.15 5.41 ± 0.69 0.0892 ± 0.0088 25.17 ± 7.21 0.420 ± 0.146 2.57 ± 0.39 2.62 ± 0.39 543.92 ± 44.43 90.65 ± 7.41
Data are shown as mean ± SD, n ¼ 12. norm, Normalized for dose and body weight (mg kg1). a Significantly different between two doses (p50.05). b Significantly different between two genders (p50.05).
Figure 3. Mean accumulative urinary recovery–time profiles of peramivir in healthy Chinese subjects after single i.v. doses of 300 and 600 mg peramivir. Data are shown as mean + SD (n ¼ 12).
Overall, peramivir was generally well tolerated in healthy Chinese subjects following single i.v. doses of 300 and 600 mg peramivir. Pharmacokinetics Mean plasma concentration–time profiles and mean accumulative urinary recovery-time profiles of peramivir in healthy Chinese subjects after single i.v. doses of 300 and 600 mg peramivir are displayed in Figures 2 and 3, respectively, with the main pharmacokinetic parameters, and the urinary
excretion amount and the accumulative urinary recovery within 36 h summarized in Table 2. No significant differences in the pharmacokinetic parameters of peramivir except Cmax were found between genders. Cmax of peramivir in female and male subjects after single i.v. dose of 300 mg peramivir were 23.3 ± 4.4 and 19.6 ± 1.7 mgL1, and were 43.4 ± 5.5 and 38.9 ± 4.4 mgL1 after single i.v. dose of 600 mg peramivir, respectively. Female subjects represented higher Cmax compared with male subjects. This might result from the significant differences in body weight between genders. After correction for body weight, there was no gender-related significant difference in Cmax of peramivir. In addition, the intra-subject and inter-subject CV for AUC0–t, AUC0–1, and Cmax of peramivir were 7.1% and 11.7%, 7.1% and 11.6%, and 13.5% and 6.2%, respectively. The results indicated that i.v. peramivir was not a highly variable drug. Between two doses, the Cmax, AUC0–t, and AUC0–1 values of peramivir were significantly different, while no significant differences were found in t1/2, CL and Vd values. Meanwhile, after normalizing for dose and body weight (mgkg1), there was no significant difference in Cmax, AUC0–t, and AUC0–1 of peramivir between two doses. After single i.v. doses of 300 and 600 mg peramivir, of Cmax, AUC0–t and AUC0–1 values were 0.9480, 1.0184, and 1.0151, respectively. The 90% CI
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around of Cmax, AUC0–t and AUC0–1 values were 0.8046– 1.0913, 0.9432–1.0937, and 0.9396–1.0906, respectively, which entirely within the limit of (0.6781, 1.3219). Thus, the dose proportionality of peramivir in healthy Chinese subjects after single i.v. doses in the range of 300–600 mg could be concluded. Within 2, 4, 8, 12 and 36 h, accumulative urinary recoveries of peramivir after single i.v. doses of 300 mg peramivir were 41.60 ± 9.37%, 61.45 ± 13.83%, 79.86 ± 11.57%, 84.31 ± 11.75% and 86.51 ± 12.02%, and those after single i.v. dose of 600 mg peramivir were 43.45 ± 4.94%, 64.18 ± 7.30%, 82.79 ± 8.56%, 88.10 ± 7.39% and 90.50 ± 7.38%, respectively. There was no significant difference in the urinary recovery of peramivir between two doses and between two genders. The majority of the administrated dose was excreted in urine as unchanged drug, indicating that renal clearance was the primary elimination route of peramivir. Moreover, the CL value of peramivir was similar with creatinine clearance rate (Ccr) in normal adults. Thus, the systemic exposures of peramivir in patients with renal impairment would be expected to be higher than those in patients with normal renal function, and individualized dose regimen of peramivir and sodium chloride injection based on Ccr would be beneficial for the rational usage of the drug in renally impaired patients (Swan et al., 2009). The mean systemic exposures in patients with mild (50 mLmin1 Ccr580 mLmin1), moderate (30 mLmin1 Ccr550 mLmin1), and sever (10 mLmin1 Ccr530 mLmin1) renal impairment were about 24%, 3.4-fold, and 6-fold higher than those in patients with normal renal function, respectively (PMDA, 2013; US FDA, 2009). Therefore, no dose adjustments of peramivir were needed for the patients with mild renal impairment, and the doses of peramivir for the patients with moderate and sever renal impairment should be reduced to a quarter and one sixth of the dose used in the patients with normal renal function, respectively (PMDA, 2013; US FDA, 2009). Moreover, there was no gender-related significant difference in the main pharmacokinetic parameters and accumulative urinary recoveries of peramivir observed after single i.v. doses of 300 and 600 mg peramivir in this study, the intrasubject and inter-subject CV for AUC0–t, AUC0–1, and Cmax of peramivir were all lower than 15.0%, and the pharmacokinetic data compared well with those reported in the fact sheet of i.v. peramivir (US FDA, 2009) and in the label of RAPIACTAÕ (PMDA, 2013). Compared to primarily metabolically cleared drugs, where enzyme polymorphisms had varying frequencies, i.v. peramivir as a primarily renally cleared drug showed similar pharmacokinetic characteristic in different ethnics groups, and different genders with the similar renal function. Thus, there might be no need to conduct extensive pharmacokinetics evaluation of i.v. peramivir between different ethnics groups and between different genders, and this could speed up the universal adoption of emergency drugs such as i.v. peramivir.
Conclusion In this study, the pharmacokinetics of peramivir in healthy Chinese subjects after single i.v. doses of 300 and 600 mg
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peramivir were evaluated. In healthy Chinese subjects, peramivir was generally well tolerated, displayed linear pharmacokinetics in the range of 300–600 mg, and was primarily excreted via urine as unchanged drug.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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