Antiviral Therapy 2014; 19:511–519 (doi: 10.3851/IMP2718)
Original article Effect of the coadministration of daclatasvir on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate Marc Bifano1*, Heather Sevinsky1, Carey Hwang2, Hamza Kandoussi 3 , Hao Jiang 3 , Dennis Grasela1, Richard Bertz1 Research and Development, Bristol–Myers Squibb, Hopewell, NJ, USA Research and Development, Bristol–Myers Squibb, Princeton, NJ, USA 3 Research and Development, Bristol–Myers Squibb, Lawrenceville, NJ, USA 1 2
*Corresponding author e-mail: [email protected]
Background: Daclatasvir is a highly selective NS5A replication complex inhibitor currently in development for the treatment of chronic hepatitis C infection. Daclatasvir is active at picomolar concentrations and demonstrates in vitro activity against a broad range of HCV genotypes. The primary objective of this study was to assess the effect of daclatasvir on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate (Ortho Tri-Cyclen®). Methods: In this open-label single-sequence study, 20 healthy female subjects received ethinyl estradiol and norgestimate for three cycles, with coadministration of daclatasvir in cycle 3. Pharmacokinetics of ethinyl estradiol
and the active metabolites of norgestimate (norelgestromin and norgestrel) were assessed in cycles 2 and 3. Results: Adjusted ratios of geometric means and 90% CIs were estimated for the maximum observed plasma concentration (ethinyl estradiol 1.11 [1.02, 1.20], norelgestromin 1.06 [0.99, 1.14] and norgestrel 1.07 [0.99, 1.16]) and area under the plasma concentration–time curve in one dosing interval (ethinyl estradiol 1.01 [0.95, 1.07], norelgestromin 1.12 [1.06, 1.17] and norgestrel 1.12 [1.02, 1.23]). Conclusions: Coadministration of daclatasvir resulted in no clinically relevant effects on exposure to ethinyl estradiol, norelgestromin or norgestrel.
Introduction Up to 170 million individuals are chronically infected with HCV worldwide [1]. Chronic HCV infection is a common cause of chronic progressive liver disease and hepatocellular carcinoma [2]. Until recently, treatment with pegylated interferon (PEG-IFN)-a and the nucleoside analogue ribavirin (RBV) was the standard of care in the management of chronic HCV infection. However, sustained virological response (SVR) rates with this regimen vary depending on viral load, HCV genotype, patient demographics, disease history and host genetics. Although SVR rates of 80% can be achieved in previously treatment-naive patients with HCV genotype 2 or 3 [3,4], SVR rates are lower among those with HCV genotype 1 (40–50%) [5], and in patients with prior nonresponse to PEG-IFN-a/RBV (6–9%). PEG-IFN-a/RBV treatment is also associated with significant haematologic toxicity and frequent side effects, such as flu-like symptoms, haemolytic anaemia, fatigue and depression [4]. ©2014 International Medical Press 1359-6535 (print) 2040-2058 (online)
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The recent introduction of the HCV non-structural protein 3 (NS3) protease inhibitors, telaprevir and boceprevir, which are approved for use in combination with PEG-IFN-a/RBV for the treatment of chronic HCV genotype 1 infection, has significantly improved SVR rates in treatment-naive patients with HCV genotype 1 infection to approximately 70–75% [6,7]. However, both of these direct-acting antivirals increase the frequency and/or severity of adverse events (AEs) compared with that observed with PEG-IFN-a/RBV treatment alone. Boceprevir is associated with increased rates of anaemia and dysgeusia [8], and telaprevir with elevated rates of rash, pruritis, nausea and anaemia [9]. In addition to their clinical AE profiles, both boceprevir and telaprevir are substrates and significant inhibitors of cytochrome (CY) P450 3A (CYP3A), and are known (telaprevir) or inferred (boceprevir) to be substrates and inhibitors of the P-glycoprotein 1 (PgP) 511
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transporter [10]. As a result, both drugs are associated with a number of pharmacokinetic interactions with concomitant medications, and are contraindicated for use with CYP3A substrates, for which elevated systemic exposure is associated with an increased risk of serious AEs [8,9]. For example, telaprevir has been shown to increase the maximum observed plasma concentration (Cmax) and area under the plasma concentration– time curve (AUC) of both cyclosporine and tacrolimus when coadministered in healthy subjects as a result of telaprevir-induced CYP3A4 inhibition [11]. In addition, telaprevir and boceprevir have also been shown to reduce exposure to a number of drugs by increasing their metabolism, thus resulting in reduced efficacy [8,9]. One such pharmacokinetic interaction noted for both telaprevir and boceprevir is a reduction of ethinyl estradiol (EE) levels when taken with hormonal contraceptives, and, as a result, a warning has been issued for both drugs advising that hormonal contraception may be unreliable during (and, in the case of telaprevir, for up to 2 weeks after) treatment [8,9]. EE and norgestimate (NGM; Ortho Tri-Cyclen®, Ortho-McNeil Pharmaceutical Inc., Raritan, NJ, USA) is a commonly prescribed combination oral contraceptive containing EE and the synthetic progestin NGM, which is converted in vivo to its active metabolites norelgestromin (NGMN) and norgestrel (NG). EE is subject to extensive first-pass metabolism in both the gut and the liver, with sulfate conjugation via sulfotransferase 1E1 in the gut, contributing to approximately 60% of the first-pass effect. Once absorbed, EE is also hydroxylated by CYP3A4 and CYP2C9, with CYP2C8, CYP2C19 and CYP1A2 contributing to a lesser extent [12–14], and is glucuronidated by uridine diphosphate glucuronyltransferase (UGT) 1A1 [15]. The basis of the interaction between EE and telaprevir or boceprevir is not fully understood, but may be a multifactorial effect resulting from alterations in CYP450 activity, direct or indirect effects on UGT or sulfation, or alterations in gastrointestinal transport mechanisms. The enzymes responsible for the metabolism of NGM and its active metabolites have not been fully characterized, but it is thought that both CYP3A4 and UGTs may also be involved. The significant teratogenicity of RBV (a pregnancy category X drug) renders it contraindicated for use in pregnancy and makes effective contraception vital in women of childbearing potential who are undergoing PEG-IFN-a/RBV-containing treatment for chronic HCV infection. Thus the effects of telaprevir and boceprevir on EE-based contraceptives necessitate the use of two non-hormonal methods while the interaction is still in effect [8,9]. A number of other direct-acting antivirals for chronic HCV infection are in clinical development. 512
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Among them is daclatasvir (DCV; BMS-790052), which is a highly selective, first-in-class inhibitor of HCV NS5A, an essential component of the HCV replication complex [16,17]. DCV inhibits multiple functions of NS5A, which may explain its potent antiviral effect in vitro; DCV is active at picomolar concentrations and demonstrates in vitro activity against a broad range of HCV genotypes [18]. DCV has previously demonstrated rapid virological suppression, high SVR rates and good tolerability in combination with PEG-IFN-a/RBV among treatment-naive patients with HCV genotype 1 [19]. Clinical efficacy with DCV has also been observed in combination with asunaprevir, an NS3 protease inhibitor and the non-nucleoside inhibitor BMS-791325 [20], as well as in combination with the nucleotide inhibitor sofosbuvir (GS-7977) with and without RBV [21]. High SVR rates are also achievable in HCV genotype 1b patients with a prior null response to PEG-IFN-a/RBV when DCV is used in combination with asunaprevir [22,23]. Preclinical data indicate that DCV is a substrate and inhibitor of PgP and a substrate for CYP3A4; in vivo studies with the CYP3A4 probe substrate midazolam suggest that DCV is unlikely to alter the pharmacokinetics of CYP3A4 substrates (Bristol–Myers Squibb, unpublished data). Therefore, unlike telaprevir and boceprevir, DCV has a lower potential for causing drug–drug interactions with drugs that are metabolized via the CYP450 pathway. We herein describe a study evaluating the steady-state pharmacokinetic effects of DCV (60 mg once daily) on the active components (EE, NGMN and NG) of a concomitant combined oral contraceptive in healthy female volunteers, along with the tolerability and safety of this drug combination.
Methods Study design This was an open-label, three-cycle (lead-in cycle [cycle 1], cycle 2 and cycle 3), single sequence study in 20 healthy women of childbearing potential (clinicaltrials.gov identifier NCT00983957; Figure 1). Screening evaluations were undertaken to determine eligibility within 28 days prior to the start of the lead-in cycle (day 1). The evening prior to dosing (day 1), subjects were admitted to the clinical facility and underwent baseline evaluations. On day 1, subjects entered the lead-in cycle to ensure compliance and to synchronize subjects to the same dosing schedule. The lead-in cycle and cycle 2 consisted of a standard EE/NGM dosing schedule: daily administration in a 4-week (3 weeks on, 1 week off) cycle, in which the EE dose remains constant at 35 mg while NGM is given on an ascending dose schedule of 180 mg during week 1, 215 mg during week 2 and 250 mg during week 3. The ©2014 International Medical Press
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Inclusion and exclusion criteria
Figure 1. Study design
Treatment A: Days 1–28 EE/NGM
Treatment B: Days 29–56 EE/NGM
Treatment C: Days 57–77 EE/NGM + DCV 60 mg once daily (Days 68–77 only)
Lead-in cycle (Cycle 1)
Cycle 2
Cycle 3
PK sampling on day 49 for 24 h
PK sampling on day 77 for 24 h
Subjects received a combined oral contraceptive on days 1–28 (lead-in cycle; treatment period A), days 29–56 (cycle 2; treatment period B) and days 57–77 (cycle 3; treatment period C), with daclatasvir (DCV) coadministration on days 68–77. EE/NGM, ethinyl estradiol and norgestimate; PK, pharmacokinetic.
Healthy female subjects aged 18 to 45 years with a body mass index (BMI) of 18–32 kg/m2 and intact ovarian function were eligible for enrolment into the study. Subjects had to be receiving a stable regimen of EE/NGM for ≥3 months prior to enrolment without evidence of breakthrough bleeding, or receiving a stable regimen of a different combined oral contraceptive for ≥3 months prior to the study and willing to switch to EE/NGM for 3 months during the study. Subjects were also required to have documented, acceptable Pap smear results within 1 year prior to day 1 of the study. A negative pregnancy test within 24 h prior to the start of study medication for each cycle was also required. Subjects were required to use an acceptable barrier method of contraception during the entire study through to 4 weeks after the study.
Pharmacokinetic assessment final study cycle (cycle 3) spanned only the 3 weeks of active EE/NGM dosing. During this cycle, DCV was administered for 10 days in combination with EE/ NGM during days 68–77. DCV was dosed at 60 mg once daily, the highest anticipated therapeutic dose. A dose of 60 mg DCV was based on previous clinical experience and is within the projected therapeutic range known to be well tolerated. Pharmacokinetic sampling was undertaken on the last day of active EE/NGM dosing during cycles 2 and 3, when subjects were receiving the highest ascending dose of NGM (250 mg). Pregnancy testing, drug screening and assessment of treatment compliance were undertaken at the clinical centre at each scheduled visit after day 1 (days 28, 48, 56 and 67). During the lead-in cycle, subjects received their initial (day 1) dose at the clinical centre and thereafter continued dosing on an outpatient basis through to day 28. During cycle 2, dosing was on an outpatient basis except during days 48–50, when subjects remained at the clinical centre for assessment and 24-h pharmacokinetic sampling (pre-dose to pre-dose on days 49–50). During cycle 3, subjects received EE/NGM on an outpatient basis through to day 67. Subjects returned to the centre on day 67 and remained throughout the period of DCV dosing (that is, days 68–77). On days 77–78, 24-h pharmacokinetic sampling (pre-dose to pre-dose) was undertaken. Written informed consent was obtained from all patients prior to study procedures. The study was approved by the institutional review board of the study centre and was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice Guidelines and local regulatory requirements. Antiviral Therapy 19.5
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Pharmacokinetic assessments were performed at steady state and pharmacokinetic evaluations were based on the concentration of study drugs in plasma at the given time points in the study. The levels of EE, NG and NGMN in human plasma were assayed using validated liquid chromatography with tandem mass spectrometry. Following a liquid–liquid extraction procedure, analyte concentrations were calculated with a 1/x2 linear regression over a concentration range of 2.0–500 pg/ml for EE, 0.02–10 ng/ml for NGMN and 50–25,000 pg/ml for NG and their internal standards (17a-ethynylestradiol-2,4,16,16-d4, desacetylnorgestimate-d5 and norgestrel-d5, respectively). All measurements were performed during the period of known analyte stability. Pharmacokinetic parameters were derived from plasma concentration-versus-time data and included the following: Cmax, time of maximum observed plasma concentration (Tmax) and AUC in one dosing interval (AUCtau). Plasma concentration-versustime data were analysed by non-compartmental methods using the program Kinetica (version 4.4.1; Adept Scientific, Letchworth Garden City, Herts, UK). Actual sample collection times were used for pharmacokinetic calculations. Predose concentrations and concentrations prior to the first quantifiable concentration that were below the lower limit of quantification were treated as ‘missing’ for the calculation of summary statistics. The Cmax and Tmax were recorded directly from experimental observations; AUCtau was calculated by log- and linear-trapezoidal calculations. Summary statistics for relevant pharmacokinetic parameters of each analyte were tabulated by treatment. To assess the effect of concomitant administration of DCV on EE, NGMN and NG, Cmax and AUCtau mixedeffect models were fitted to log-transformed data with treatment as a fixed effect and measurements within 513
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each subject as repeated measurements. Log-scale point estimates and 90% CIs for treatment differences were subsequently exponentiated to obtain estimates on the original scale. If the 90% CIs for the geometric mean ratios (GMRs) for parameters obtained with versus without concomitant DCV were entirely contained within the conventional bioequivalence range of 0.80–1.25, then an absence of DCV effect on the pharmacokinetics of each analyte was concluded. No adjustments were made for multiplicity. All statistical analyses were carried out using SAS/STAT software (version 8.2; SAS Institute Inc., Cary, NC, USA).
Safety assessments Subjects were closely monitored for AEs throughout the study. Physical examinations, vital sign measurements, 12-lead electrocardiograms (ECG) and clinical laboratory evaluations were performed at selected times throughout the study. Safety measurements were based on the results of these evaluations and on medical review of AE reports.
Results Subjects A total of 20 women were enrolled and received EE/ NGM. Of these, 18 subjects completed the study. All subjects were Caucasian, with a mean age of 29.8 years (range 18–44) and a mean BMI of 24.0 kg/m2 (range 20.5–28.8) at screening.
Pharmacokinetics of EE, NGMN and NG Mean 24 h steady-state plasma concentration–time profiles for EE (Figure 2A), NGMN (Figure 2B) and NG (Figure 2C) following repeated dosing of EE/NGM with (day 77) and without (day 49) DCV are shown. For all analytes, peak values were reached 2 h post-dose and returned to baseline by 24 h post-dose. Individual intra-subject changes in Cmax and AUCtau for EE/NGM dosing with and without DCV are shown for all three analytes (Figure 3). A slight increase in EE Cmax was observed in the majority of patients during coadministration of DCV (Figure 3A), but with no clear pattern observed for AUCtau (Figure 3B). For NGMN and NG, a slight increase in AUCtau was observed in most subjects, with no clear pattern observed for Cmax (Figure 3C–3F). Statistical comparisons of the geometric mean values for Cmax and AUCtau (0–24 h post-dose) are shown for all three analytes (Table 1). In all cases, the 90% CIs for the GMRs for dosing with versus without concomitant DCV fell within the pre-specified range denoting no interaction (0.8–1.25). GMR 90% CI lower boundaries for EE Cmax, NGMN AUCtau and NG AUCtau were 1.02, 1.06 and 1.02, respectively, indicating small increases 514
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in exposure when DCV was coadministered with EE/ NGM; however, the upper boundaries remained within the pre-defined no-effect range.
Safety No serious AEs were reported. One subject discontinued study treatment as a result of back injury, which was not related to study treatments. Another subject discontinued for personal reasons. The most common AEs (those occurring in ≥10% of patients during any treatment period) are shown (Table 2). All AEs reported throughout the treatment periods were classified as mild in intensity. The most common AEs were headache, metrorrhagia, constipation and back pain. All subjects who experienced metrorrhagia (30% of total subjects) throughout the treatment periods had switched to EE/NGM from other oral contraceptives. All subjects who also experienced metrorrhagia during treatment period C (days 68–77; DCV coadministration) had experienced this AE during earlier treatment periods. No laboratory AEs were reported and no evidence of clinically meaningful effects on physical examinations, ECGs or vital sign measurements were observed.
Discussion Pharmacokinetic interactions with oral contraceptives that necessitate additional or alternative methods of birth control during treatment are common among drugs with significant inhibitory or inductive effects on CYP3A4 and/or UGT. These include many HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors [24], which, unlike the finite HCV treatments, require life-long administration. Oral contraceptive failure or reductions in efficacy are frequent causes of unwanted pregnancy or breakthrough bleeding, and may result from drug–drug interactions that increase EE or NGM metabolism. For example, studies of the HIV protease inhibitors atazanavir and darunavir in combination with ritonavir reduce EE exposures [25,26]. Although ritonavir is both an inhibitor of CYP3A4 and an inducer of UGT, through activation of the pregnane x receptor, the increased clearance of EE with coadministration of ritonavir suggests that clearance via UGT may be more important in the disposition of EE than CYP3A4 [27,28]. The anticonvulsant carbamazepine is also a known inducer of UGT and CYP3A4 [29]. Coadministration of carbamazepine with an EE-containing oral contraceptive results in reduced EE exposures, and increased ovulation and breakthrough bleeding, compared with that observed with administration of the oral contraceptive alone [30]. The currently approved direct-acting HCV antivirals, telaprevir and boceprevir, are significant inhibitors and ©2014 International Medical Press
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Figure 2. Mean plasma concentration–time profiles of ethinyl estradiol, norelgestromin and norgestrel
A
EE/NGM on day 49 (n=20)
EE/NGM+DCV 60 mg once daily on day 77 (n=18)
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Time, h Mean (±sd) plasma concentration–time profiles of (A) ethinyl estradiol, (B) norelgestromin and (C) norgestrel when a combined oral contraceptive is administered alone (day 49) and in combination with the NS5A replication complex inhibitor daclatasvir (DCV; 60 mg once daily, day 77) in healthy female subjects. EE/NGM, ethinyl estradiol and norgestimate. Antiviral Therapy 19.5
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Figure 3. Cmax and AUCtau plots for ethinyl estradiol, norelgestromin and norgestrel
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Individual maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve in one dosing interval (AUCtau; 0–24 h post-dose) plots for (A&B) ethinyl estradiol, (C&D) norelgestromin and (E&F) norgestrel when a combined oral contraceptive is administered alone (day 49) and in combination with the NS5A replication complex inhibitor daclatasvir (DCV; 60 mg once daily; day 77) in healthy female subjects. EE/NGM, ethinyl estradiol and norgestimate. 516
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Table 1. Pharmacokinetic comparisons of ethinyl estradiol, norelgestromin and norgestrel for a combined oral contraceptive containing EE/NGM dosed with versus without concomitant DCV Adjusted geometric means EE/NGM alone (day 49) EE/NGM+DCV (day 77)
GMR (90% CI), with versus without DCV
Ethinyl estradiol Cmax, pg/ml 118.53 131.03 1.11 (1.02, 1.20) AUCtau, pg•h/ml 959.37 968.03 1.01 (0.95, 1.07) Norelgestromin Cmax, ng/ml 1.99 2.11 1.06 (0.99, 1.14) AUCtau, ng•h/ml 15.38 17.15 1.12 (1.06, 1.17) Norgestrel Cmax, pg/ml 2,674.69 2,864.03 1.07 (0.99, 1.16) AUCtau, pg•h/ml 47,258.35 52,958.98 1.12 (1.02, 1.23) AUCtau, area under the plasma concentration–time curve in one dosing interval (0–24 h post-dose); Cmax, maximum observed plasma concentration; DCV, daclatasvir; EE/NGM, ethinyl estradiol and norgestimate; GMR, geometric mean ratio.
Table 2. Summary of adverse events occurring in ≥10% patients in any treatment period Adverse event
Treatment period A EE/NGM days 1–28a
Treatment period B Treatment period C EE/NGM EE/NGM EE/NGM EE/NGM+DCV days 29–46a days 47–56a days 57–67b days 68–77b
Headache Metrorrhagia Constipation Back pain Nausea Irregular menstruation Acne Abdominal pain
4 (20.0) 5 (25.0) 0 0 0 2 (10.0) 0 2 (10.0)
2 (10.0) 1 (5.0) 0 1 (5.0) 0 0 0 0
6 (30.0) 1 (5.0) 0 0 2 (10.0) 1 (5.0) 0 0
0 0 0 0 0 0 2 (11) 0
3 (16.7) 3 (16.7) 4 (22.2) 3 (16.7) 1 (5.6) 0 0 0
Data are n (%). an=20. bn=18. DCV, daclatasvir; EE/NGM, ethinyl estradiol and norgestimate.
substrates of CYP3A4 and have been demonstrated to increase exposure to a number of CYP3A4 substrates, including the calcineurin inhibitors cyclosporine and tacrolimus, when coadministered with telaprevir [11]. By contrast, coadministration of telaprevir and an EE/ norethindrone‑containing contraceptive results in a 26% reduction in EE Cmax, 28% reduction in EE AUC, and 33% reduction in EE Cmin, which may be due to telaprevir increasing first-pass metabolism of EE in the gastrointestinal tract by affecting transporters involved in the absorption of EE [31]. Similarly, boceprevir also reduces EE AUC by 24%, while increasing the Cmax and AUC of the synthetic progestin drospirenone by 99% and 57%, respectively, substantially increasing the risk of drospirenone-related AEs [10]. The drug–drug interactions observed between telaprevir and boceprevir and EE-based contraceptives necessitate the use of two nonhormonal methods of contraception during, and for telaprevir up to 2 weeks after, treatment. Ongoing clinical development of other direct-acting antivirals for HCV infection requires that their potential for drug interactions with concomitant medications is investigated. Antiviral Therapy 19.5
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Knowledge of their oral contraceptive interactions is vital given the known teratogenic and embryocidal potential of RBV and the likelihood that these newer agents will frequently be used in PEG‑IFN‑a/ RBV-containing combinations. Few studies specifically discuss what constitutes a subtherapeutic level of EE. However, most oral contraceptives typically contain EE at a dose of 30–35 µg, with low-dose contraceptives containing 20–25 µg of EE. Furthermore, it is not uncommon for upward dose titration to occur in the context of low-dose EE for breakthrough bleeding. Therefore, any drug–drug interactions resulting in EE levels less than those achieved with a 20 µg dose are likely to result in reduced efficacy, and potentially breakthrough bleeding [25]. In addition, it is generally accepted that even minor decreases (arbitrary definition ≤20% reduction in exposure; equivalent to a decrease from 30 µg to 20 µg of EE) in EE Cmax and AUCtau may result in a loss of contraceptive efficacy; therefore, where this occurs, patients are advised to use non-hormonal methods of contraception to prevent pregnancy [32]. 517
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The main objective of this study was to assess the effect of the investigational NS5A replication complex inhibitor DCV on the pharmacokinetics of EE and NGMN, the primary active components of a combined oral contraceptive, in healthy female subjects. Previously, DCV has demonstrated weak time-dependent inhibition of CYP3A4 in vitro, although subsequent in vitro work identified a low potential for CYP3A4 induction based on increased CYP3A4 messenger RNA activity in human hepatocytes (Bristol–Myers Squibb, unpublished data). Results from a clinical study assessing the impact of DCV on the pharmacokinetics of the CYP3A4 substrate midazolam demonstrated that DCV is unlikely to have a clinically significant impact on exposures to CYP3A4 substrates (Bristol–Myers Squibb, unpublished data). The potential for an interaction between DCV and substrates of sulfotransferase or UGTs has not been investigated. Unlike the reductions in EE exposure observed with concomitant telaprevir and boceprevir, in the current study only small increases (6–11% increase in GMR) in the Cmax of EE, NGMN and NG were observed with combined dosing of EE/NGM and DCV, and, similarly, modest increases (approximately 12%) in the AUCtau of NGMN and NG. All comparisons fell within the prespecified range for no effect (90% CIs for GMRs contained within the conventional bioequivalence range of 0.8–1.25), indicating that DCV does not have any clinically relevant effects on any active component of EE/NGM. In addition, coadministration of DCV with EE/NGM did not increase the frequency of metrorrhagia observed or change the individuals affected during cycle 3 compared with the administration of EE/NGM alone (cycles 1 and 2), suggesting maintenance of contraceptive efficacy of EE/NGM during DCV coadministration. Administration of DCV in combination with a combined oral contraceptive was also well tolerated in this study, with no serious or life-threatening AEs or AE-related discontinuations. Most AEs recorded were mild in intensity and were comparable to those observed during DCV monotherapy in HCV-infected patients [33]. Assessing the effect of anti-HCV drugs on the efficacy on oral contraceptives is a challenging undertaking. Most drug–drug interaction studies investigate only two drugs at a time to enable interpretation of any changes in pharmacokinetic parameters. However, assessing the effect of anti-HCV drugs, including DCV, individually does not reflect their real-world application as part of combination treatment regimens, when there may be multiple layers of enzyme induction or inhibition as well as other physiologic effects that may alter drug absorption or excretion. Indeed, future assessments looking at combination DAAs and oral contraceptive drug–drug interactions may be warranted to reflect the clinical 518
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use of these new agents. There are also disadvantages to conducting this, and other pharmacokinetic studies, in healthy HCV-negative subjects, who typically have lower BMIs and normal liver function compared with HCV-infected patients, which may have implications for drug metabolism and drug–drug interactions. In addition, most drug–drug interaction studies, including the current study, investigate only one type of oral contraceptive. Although the results from the current study suggest that DCV is unlikely to have any clinically meaningful effects on other EE-based oral contraceptives, it cannot be fully ascertained from the results presented herein that DCV will not have any effects on any other oral contraceptives that are currently available. In conclusion, the results of this study indicate that coadministration of DCV and an oral contraceptive containing EE and a progestin is well tolerated, does not result in clinically significant changes in exposure to either component, and hence, a loss of contraceptive efficacy due to a pharmacokinetic interaction is unlikely.
Acknowledgements Editorial assistance was provided by Kate Gaffey of Articulate Science (Manchester, UK) and was funded by Bristol–Myers Squibb. All authors wrote the manuscript. MB, DG and RB designed the research. MB, HS and CH analysed the data. HK and HJ contributed new reagents/ analytical tools.
Disclosure statement All authors are employees of Bristol–Myers Squibb.
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Poordad F, McCone J, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1195–1206. Victrelis (boceprevir). Package insert 2012. Merck & Co., Inc., NJ, USA. Incivek (telaprevir). Package insert 2012. Vertex Pharmaceuticals Incorporated, MA, USA. Wilby KJ, Greanya ED, Ford JA, Yoshida EM, Partovi N. A review of drug interactions with boceprevir and telaprevir: implications for HIV and transplant patients. Ann Hepatol 2012; 11:179–185. Garg V, van Heeswijk R, Lee JE, Alves K, Nadkarni P, Luo X. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology 2011; 54:20–27. Hirai S, Hussain A, Haddadin M, Smith RB. First-pass metabolism of ethinyl estradiol in dogs and rats. J Pharm Sci 1981; 70:403–406. Guengerich FP. Oxidation of 17 alpha-ethynylestradiol by human liver cytochrome P-450. Mol Pharmacol 1988; 33:500–508. Wang B, Sanchez RI, Franklin RB, Evans DC, Huskey SE. The involvement of CYP3A4 and CYP2C9 in the metabolism of 17 alpha-ethinylestradiol. Drug Metab Dispos 2004; 32:1209–1212. Ebner T, Remmel RP, Burchell B. Human bilirubin UDPglucuronosyltransferase catalyzes the glucuronidation of ethinylestradiol. Mol Pharmacol 1993; 43:649–654. Bukh J, Pietschmann T, Lohmann V, et al. Mutations that permit efficient replication of hepatitis C virus RNA in Huh-7 cells prevent productive replication in chimpanzees. Proc Natl Acad Sci US 2002; 99:14416–14421. Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature 2005; 436:933–938. Gao M, Nettles RE, Belema M, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature 2010; 465:96–100. Pol S, Ghalib RH, Rustig VK, et al. Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial. Lancet Infect Dis 2012; 12:671–677. Everson GT, Sims KD, Rodriguez-Torres M, et al. Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection. Gastroenterology 2014; 146:420–429. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014; 370:211–221.
22. Chayama K, Takahashi S, Toyota J, et al. Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders. Hepatology 2012; 55:742–748. 23. Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012; 366:216–224. 24. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. (Accessed 8 June 2012). Available from http://aidsinfo.nih.gov/guidelines 25. Zhang J, Chung E, Yones C, et al. The effect of atazanavir/ ritonavir on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy women. Antivir Ther 2011; 16:157–164. 26. Sekar VJ, Lefebvre E, Guzman SS, et al. Pharmacokinetic interaction between ethinyl estradiol, norethindrone and darunavir with low-dose ritonavir in healthy women. Antivir Ther 2008; 13:563–569. 27. Sonoda J, Xie W, Rosenfeld JM, Barwick JL, Guzelian PS, Evans RM. Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR). Proc Natl Acad Sci U S A 2002; 99:13801–13806. 28. Luo G, Cunningham M, Kim S, et al. CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. Drug Metab Dispos 2002; 30:795–804. 29. Anderson GD. A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother 1998; 32:554–563. 30. Davis AR, Westhoff CL, Stanczyk FZ. Carbamazepine coadministration with an oral contraceptive: effects on steroid pharmacokinetics, ovulation, and bleeding. Epilepsia 2011; 52:243–247. 31. Garg V, van Heeswijk R, Yang Y, Kauffman R, Smith F, Adda N. The pharmacokinetic interaction between an oral contraceptive containing ethinyl estradiol and norethindrone and the HCV protease inhibitor telaprevir. J Clin Pharmacol 2012; 52:1574–1583. 32. Royal College of Obstetricians and Gynaecologists. Faculty of Sexual And Reproductive Healthcare clinical guidance. Drug interactions with hormonal contraception: clinical effectiveness unit. (Updated January 2012. Accessed October 2013.) Available from http://www.fsrh.org/pdfs/ CEUguidancedruginteractionshormonal.pdf 33. Nettles RE, Gao M, Bifano M, et al. Multiple ascending dose study of BMS-790052, an NS5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1. Hepatology 2011; 54:1956–1965.
Accepted 26 November 2013; published online 17 December 2013
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Original article Effect of the coadministration of daclatasvir on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate Marc Bifano1*, Heather Sevinsky1, Carey Hwang2, Hamza Kandoussi 3 , Hao Jiang 3 , Dennis Grasela1, Richard Bertz1 Research and Development, Bristol–Myers Squibb, Hopewell, NJ, USA Research and Development, Bristol–Myers Squibb, Princeton, NJ, USA 3 Research and Development, Bristol–Myers Squibb, Lawrenceville, NJ, USA 1 2
*Corresponding author e-mail: [email protected]
Background: Daclatasvir is a highly selective NS5A replication complex inhibitor currently in development for the treatment of chronic hepatitis C infection. Daclatasvir is active at picomolar concentrations and demonstrates in vitro activity against a broad range of HCV genotypes. The primary objective of this study was to assess the effect of daclatasvir on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate (Ortho Tri-Cyclen®). Methods: In this open-label single-sequence study, 20 healthy female subjects received ethinyl estradiol and norgestimate for three cycles, with coadministration of daclatasvir in cycle 3. Pharmacokinetics of ethinyl estradiol
and the active metabolites of norgestimate (norelgestromin and norgestrel) were assessed in cycles 2 and 3. Results: Adjusted ratios of geometric means and 90% CIs were estimated for the maximum observed plasma concentration (ethinyl estradiol 1.11 [1.02, 1.20], norelgestromin 1.06 [0.99, 1.14] and norgestrel 1.07 [0.99, 1.16]) and area under the plasma concentration–time curve in one dosing interval (ethinyl estradiol 1.01 [0.95, 1.07], norelgestromin 1.12 [1.06, 1.17] and norgestrel 1.12 [1.02, 1.23]). Conclusions: Coadministration of daclatasvir resulted in no clinically relevant effects on exposure to ethinyl estradiol, norelgestromin or norgestrel.
Introduction Up to 170 million individuals are chronically infected with HCV worldwide [1]. Chronic HCV infection is a common cause of chronic progressive liver disease and hepatocellular carcinoma [2]. Until recently, treatment with pegylated interferon (PEG-IFN)-a and the nucleoside analogue ribavirin (RBV) was the standard of care in the management of chronic HCV infection. However, sustained virological response (SVR) rates with this regimen vary depending on viral load, HCV genotype, patient demographics, disease history and host genetics. Although SVR rates of 80% can be achieved in previously treatment-naive patients with HCV genotype 2 or 3 [3,4], SVR rates are lower among those with HCV genotype 1 (40–50%) [5], and in patients with prior nonresponse to PEG-IFN-a/RBV (6–9%). PEG-IFN-a/RBV treatment is also associated with significant haematologic toxicity and frequent side effects, such as flu-like symptoms, haemolytic anaemia, fatigue and depression [4]. ©2014 International Medical Press 1359-6535 (print) 2040-2058 (online)
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The recent introduction of the HCV non-structural protein 3 (NS3) protease inhibitors, telaprevir and boceprevir, which are approved for use in combination with PEG-IFN-a/RBV for the treatment of chronic HCV genotype 1 infection, has significantly improved SVR rates in treatment-naive patients with HCV genotype 1 infection to approximately 70–75% [6,7]. However, both of these direct-acting antivirals increase the frequency and/or severity of adverse events (AEs) compared with that observed with PEG-IFN-a/RBV treatment alone. Boceprevir is associated with increased rates of anaemia and dysgeusia [8], and telaprevir with elevated rates of rash, pruritis, nausea and anaemia [9]. In addition to their clinical AE profiles, both boceprevir and telaprevir are substrates and significant inhibitors of cytochrome (CY) P450 3A (CYP3A), and are known (telaprevir) or inferred (boceprevir) to be substrates and inhibitors of the P-glycoprotein 1 (PgP) 511
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transporter [10]. As a result, both drugs are associated with a number of pharmacokinetic interactions with concomitant medications, and are contraindicated for use with CYP3A substrates, for which elevated systemic exposure is associated with an increased risk of serious AEs [8,9]. For example, telaprevir has been shown to increase the maximum observed plasma concentration (Cmax) and area under the plasma concentration– time curve (AUC) of both cyclosporine and tacrolimus when coadministered in healthy subjects as a result of telaprevir-induced CYP3A4 inhibition [11]. In addition, telaprevir and boceprevir have also been shown to reduce exposure to a number of drugs by increasing their metabolism, thus resulting in reduced efficacy [8,9]. One such pharmacokinetic interaction noted for both telaprevir and boceprevir is a reduction of ethinyl estradiol (EE) levels when taken with hormonal contraceptives, and, as a result, a warning has been issued for both drugs advising that hormonal contraception may be unreliable during (and, in the case of telaprevir, for up to 2 weeks after) treatment [8,9]. EE and norgestimate (NGM; Ortho Tri-Cyclen®, Ortho-McNeil Pharmaceutical Inc., Raritan, NJ, USA) is a commonly prescribed combination oral contraceptive containing EE and the synthetic progestin NGM, which is converted in vivo to its active metabolites norelgestromin (NGMN) and norgestrel (NG). EE is subject to extensive first-pass metabolism in both the gut and the liver, with sulfate conjugation via sulfotransferase 1E1 in the gut, contributing to approximately 60% of the first-pass effect. Once absorbed, EE is also hydroxylated by CYP3A4 and CYP2C9, with CYP2C8, CYP2C19 and CYP1A2 contributing to a lesser extent [12–14], and is glucuronidated by uridine diphosphate glucuronyltransferase (UGT) 1A1 [15]. The basis of the interaction between EE and telaprevir or boceprevir is not fully understood, but may be a multifactorial effect resulting from alterations in CYP450 activity, direct or indirect effects on UGT or sulfation, or alterations in gastrointestinal transport mechanisms. The enzymes responsible for the metabolism of NGM and its active metabolites have not been fully characterized, but it is thought that both CYP3A4 and UGTs may also be involved. The significant teratogenicity of RBV (a pregnancy category X drug) renders it contraindicated for use in pregnancy and makes effective contraception vital in women of childbearing potential who are undergoing PEG-IFN-a/RBV-containing treatment for chronic HCV infection. Thus the effects of telaprevir and boceprevir on EE-based contraceptives necessitate the use of two non-hormonal methods while the interaction is still in effect [8,9]. A number of other direct-acting antivirals for chronic HCV infection are in clinical development. 512
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Among them is daclatasvir (DCV; BMS-790052), which is a highly selective, first-in-class inhibitor of HCV NS5A, an essential component of the HCV replication complex [16,17]. DCV inhibits multiple functions of NS5A, which may explain its potent antiviral effect in vitro; DCV is active at picomolar concentrations and demonstrates in vitro activity against a broad range of HCV genotypes [18]. DCV has previously demonstrated rapid virological suppression, high SVR rates and good tolerability in combination with PEG-IFN-a/RBV among treatment-naive patients with HCV genotype 1 [19]. Clinical efficacy with DCV has also been observed in combination with asunaprevir, an NS3 protease inhibitor and the non-nucleoside inhibitor BMS-791325 [20], as well as in combination with the nucleotide inhibitor sofosbuvir (GS-7977) with and without RBV [21]. High SVR rates are also achievable in HCV genotype 1b patients with a prior null response to PEG-IFN-a/RBV when DCV is used in combination with asunaprevir [22,23]. Preclinical data indicate that DCV is a substrate and inhibitor of PgP and a substrate for CYP3A4; in vivo studies with the CYP3A4 probe substrate midazolam suggest that DCV is unlikely to alter the pharmacokinetics of CYP3A4 substrates (Bristol–Myers Squibb, unpublished data). Therefore, unlike telaprevir and boceprevir, DCV has a lower potential for causing drug–drug interactions with drugs that are metabolized via the CYP450 pathway. We herein describe a study evaluating the steady-state pharmacokinetic effects of DCV (60 mg once daily) on the active components (EE, NGMN and NG) of a concomitant combined oral contraceptive in healthy female volunteers, along with the tolerability and safety of this drug combination.
Methods Study design This was an open-label, three-cycle (lead-in cycle [cycle 1], cycle 2 and cycle 3), single sequence study in 20 healthy women of childbearing potential (clinicaltrials.gov identifier NCT00983957; Figure 1). Screening evaluations were undertaken to determine eligibility within 28 days prior to the start of the lead-in cycle (day 1). The evening prior to dosing (day 1), subjects were admitted to the clinical facility and underwent baseline evaluations. On day 1, subjects entered the lead-in cycle to ensure compliance and to synchronize subjects to the same dosing schedule. The lead-in cycle and cycle 2 consisted of a standard EE/NGM dosing schedule: daily administration in a 4-week (3 weeks on, 1 week off) cycle, in which the EE dose remains constant at 35 mg while NGM is given on an ascending dose schedule of 180 mg during week 1, 215 mg during week 2 and 250 mg during week 3. The ©2014 International Medical Press
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Inclusion and exclusion criteria
Figure 1. Study design
Treatment A: Days 1–28 EE/NGM
Treatment B: Days 29–56 EE/NGM
Treatment C: Days 57–77 EE/NGM + DCV 60 mg once daily (Days 68–77 only)
Lead-in cycle (Cycle 1)
Cycle 2
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PK sampling on day 49 for 24 h
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Subjects received a combined oral contraceptive on days 1–28 (lead-in cycle; treatment period A), days 29–56 (cycle 2; treatment period B) and days 57–77 (cycle 3; treatment period C), with daclatasvir (DCV) coadministration on days 68–77. EE/NGM, ethinyl estradiol and norgestimate; PK, pharmacokinetic.
Healthy female subjects aged 18 to 45 years with a body mass index (BMI) of 18–32 kg/m2 and intact ovarian function were eligible for enrolment into the study. Subjects had to be receiving a stable regimen of EE/NGM for ≥3 months prior to enrolment without evidence of breakthrough bleeding, or receiving a stable regimen of a different combined oral contraceptive for ≥3 months prior to the study and willing to switch to EE/NGM for 3 months during the study. Subjects were also required to have documented, acceptable Pap smear results within 1 year prior to day 1 of the study. A negative pregnancy test within 24 h prior to the start of study medication for each cycle was also required. Subjects were required to use an acceptable barrier method of contraception during the entire study through to 4 weeks after the study.
Pharmacokinetic assessment final study cycle (cycle 3) spanned only the 3 weeks of active EE/NGM dosing. During this cycle, DCV was administered for 10 days in combination with EE/ NGM during days 68–77. DCV was dosed at 60 mg once daily, the highest anticipated therapeutic dose. A dose of 60 mg DCV was based on previous clinical experience and is within the projected therapeutic range known to be well tolerated. Pharmacokinetic sampling was undertaken on the last day of active EE/NGM dosing during cycles 2 and 3, when subjects were receiving the highest ascending dose of NGM (250 mg). Pregnancy testing, drug screening and assessment of treatment compliance were undertaken at the clinical centre at each scheduled visit after day 1 (days 28, 48, 56 and 67). During the lead-in cycle, subjects received their initial (day 1) dose at the clinical centre and thereafter continued dosing on an outpatient basis through to day 28. During cycle 2, dosing was on an outpatient basis except during days 48–50, when subjects remained at the clinical centre for assessment and 24-h pharmacokinetic sampling (pre-dose to pre-dose on days 49–50). During cycle 3, subjects received EE/NGM on an outpatient basis through to day 67. Subjects returned to the centre on day 67 and remained throughout the period of DCV dosing (that is, days 68–77). On days 77–78, 24-h pharmacokinetic sampling (pre-dose to pre-dose) was undertaken. Written informed consent was obtained from all patients prior to study procedures. The study was approved by the institutional review board of the study centre and was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice Guidelines and local regulatory requirements. Antiviral Therapy 19.5
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Pharmacokinetic assessments were performed at steady state and pharmacokinetic evaluations were based on the concentration of study drugs in plasma at the given time points in the study. The levels of EE, NG and NGMN in human plasma were assayed using validated liquid chromatography with tandem mass spectrometry. Following a liquid–liquid extraction procedure, analyte concentrations were calculated with a 1/x2 linear regression over a concentration range of 2.0–500 pg/ml for EE, 0.02–10 ng/ml for NGMN and 50–25,000 pg/ml for NG and their internal standards (17a-ethynylestradiol-2,4,16,16-d4, desacetylnorgestimate-d5 and norgestrel-d5, respectively). All measurements were performed during the period of known analyte stability. Pharmacokinetic parameters were derived from plasma concentration-versus-time data and included the following: Cmax, time of maximum observed plasma concentration (Tmax) and AUC in one dosing interval (AUCtau). Plasma concentration-versustime data were analysed by non-compartmental methods using the program Kinetica (version 4.4.1; Adept Scientific, Letchworth Garden City, Herts, UK). Actual sample collection times were used for pharmacokinetic calculations. Predose concentrations and concentrations prior to the first quantifiable concentration that were below the lower limit of quantification were treated as ‘missing’ for the calculation of summary statistics. The Cmax and Tmax were recorded directly from experimental observations; AUCtau was calculated by log- and linear-trapezoidal calculations. Summary statistics for relevant pharmacokinetic parameters of each analyte were tabulated by treatment. To assess the effect of concomitant administration of DCV on EE, NGMN and NG, Cmax and AUCtau mixedeffect models were fitted to log-transformed data with treatment as a fixed effect and measurements within 513
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each subject as repeated measurements. Log-scale point estimates and 90% CIs for treatment differences were subsequently exponentiated to obtain estimates on the original scale. If the 90% CIs for the geometric mean ratios (GMRs) for parameters obtained with versus without concomitant DCV were entirely contained within the conventional bioequivalence range of 0.80–1.25, then an absence of DCV effect on the pharmacokinetics of each analyte was concluded. No adjustments were made for multiplicity. All statistical analyses were carried out using SAS/STAT software (version 8.2; SAS Institute Inc., Cary, NC, USA).
Safety assessments Subjects were closely monitored for AEs throughout the study. Physical examinations, vital sign measurements, 12-lead electrocardiograms (ECG) and clinical laboratory evaluations were performed at selected times throughout the study. Safety measurements were based on the results of these evaluations and on medical review of AE reports.
Results Subjects A total of 20 women were enrolled and received EE/ NGM. Of these, 18 subjects completed the study. All subjects were Caucasian, with a mean age of 29.8 years (range 18–44) and a mean BMI of 24.0 kg/m2 (range 20.5–28.8) at screening.
Pharmacokinetics of EE, NGMN and NG Mean 24 h steady-state plasma concentration–time profiles for EE (Figure 2A), NGMN (Figure 2B) and NG (Figure 2C) following repeated dosing of EE/NGM with (day 77) and without (day 49) DCV are shown. For all analytes, peak values were reached 2 h post-dose and returned to baseline by 24 h post-dose. Individual intra-subject changes in Cmax and AUCtau for EE/NGM dosing with and without DCV are shown for all three analytes (Figure 3). A slight increase in EE Cmax was observed in the majority of patients during coadministration of DCV (Figure 3A), but with no clear pattern observed for AUCtau (Figure 3B). For NGMN and NG, a slight increase in AUCtau was observed in most subjects, with no clear pattern observed for Cmax (Figure 3C–3F). Statistical comparisons of the geometric mean values for Cmax and AUCtau (0–24 h post-dose) are shown for all three analytes (Table 1). In all cases, the 90% CIs for the GMRs for dosing with versus without concomitant DCV fell within the pre-specified range denoting no interaction (0.8–1.25). GMR 90% CI lower boundaries for EE Cmax, NGMN AUCtau and NG AUCtau were 1.02, 1.06 and 1.02, respectively, indicating small increases 514
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in exposure when DCV was coadministered with EE/ NGM; however, the upper boundaries remained within the pre-defined no-effect range.
Safety No serious AEs were reported. One subject discontinued study treatment as a result of back injury, which was not related to study treatments. Another subject discontinued for personal reasons. The most common AEs (those occurring in ≥10% of patients during any treatment period) are shown (Table 2). All AEs reported throughout the treatment periods were classified as mild in intensity. The most common AEs were headache, metrorrhagia, constipation and back pain. All subjects who experienced metrorrhagia (30% of total subjects) throughout the treatment periods had switched to EE/NGM from other oral contraceptives. All subjects who also experienced metrorrhagia during treatment period C (days 68–77; DCV coadministration) had experienced this AE during earlier treatment periods. No laboratory AEs were reported and no evidence of clinically meaningful effects on physical examinations, ECGs or vital sign measurements were observed.
Discussion Pharmacokinetic interactions with oral contraceptives that necessitate additional or alternative methods of birth control during treatment are common among drugs with significant inhibitory or inductive effects on CYP3A4 and/or UGT. These include many HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors [24], which, unlike the finite HCV treatments, require life-long administration. Oral contraceptive failure or reductions in efficacy are frequent causes of unwanted pregnancy or breakthrough bleeding, and may result from drug–drug interactions that increase EE or NGM metabolism. For example, studies of the HIV protease inhibitors atazanavir and darunavir in combination with ritonavir reduce EE exposures [25,26]. Although ritonavir is both an inhibitor of CYP3A4 and an inducer of UGT, through activation of the pregnane x receptor, the increased clearance of EE with coadministration of ritonavir suggests that clearance via UGT may be more important in the disposition of EE than CYP3A4 [27,28]. The anticonvulsant carbamazepine is also a known inducer of UGT and CYP3A4 [29]. Coadministration of carbamazepine with an EE-containing oral contraceptive results in reduced EE exposures, and increased ovulation and breakthrough bleeding, compared with that observed with administration of the oral contraceptive alone [30]. The currently approved direct-acting HCV antivirals, telaprevir and boceprevir, are significant inhibitors and ©2014 International Medical Press
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Figure 2. Mean plasma concentration–time profiles of ethinyl estradiol, norelgestromin and norgestrel
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Time, h Mean (±sd) plasma concentration–time profiles of (A) ethinyl estradiol, (B) norelgestromin and (C) norgestrel when a combined oral contraceptive is administered alone (day 49) and in combination with the NS5A replication complex inhibitor daclatasvir (DCV; 60 mg once daily, day 77) in healthy female subjects. EE/NGM, ethinyl estradiol and norgestimate. Antiviral Therapy 19.5
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Figure 3. Cmax and AUCtau plots for ethinyl estradiol, norelgestromin and norgestrel
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Individual maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve in one dosing interval (AUCtau; 0–24 h post-dose) plots for (A&B) ethinyl estradiol, (C&D) norelgestromin and (E&F) norgestrel when a combined oral contraceptive is administered alone (day 49) and in combination with the NS5A replication complex inhibitor daclatasvir (DCV; 60 mg once daily; day 77) in healthy female subjects. EE/NGM, ethinyl estradiol and norgestimate. 516
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Table 1. Pharmacokinetic comparisons of ethinyl estradiol, norelgestromin and norgestrel for a combined oral contraceptive containing EE/NGM dosed with versus without concomitant DCV Adjusted geometric means EE/NGM alone (day 49) EE/NGM+DCV (day 77)
GMR (90% CI), with versus without DCV
Ethinyl estradiol Cmax, pg/ml 118.53 131.03 1.11 (1.02, 1.20) AUCtau, pg•h/ml 959.37 968.03 1.01 (0.95, 1.07) Norelgestromin Cmax, ng/ml 1.99 2.11 1.06 (0.99, 1.14) AUCtau, ng•h/ml 15.38 17.15 1.12 (1.06, 1.17) Norgestrel Cmax, pg/ml 2,674.69 2,864.03 1.07 (0.99, 1.16) AUCtau, pg•h/ml 47,258.35 52,958.98 1.12 (1.02, 1.23) AUCtau, area under the plasma concentration–time curve in one dosing interval (0–24 h post-dose); Cmax, maximum observed plasma concentration; DCV, daclatasvir; EE/NGM, ethinyl estradiol and norgestimate; GMR, geometric mean ratio.
Table 2. Summary of adverse events occurring in ≥10% patients in any treatment period Adverse event
Treatment period A EE/NGM days 1–28a
Treatment period B Treatment period C EE/NGM EE/NGM EE/NGM EE/NGM+DCV days 29–46a days 47–56a days 57–67b days 68–77b
Headache Metrorrhagia Constipation Back pain Nausea Irregular menstruation Acne Abdominal pain
4 (20.0) 5 (25.0) 0 0 0 2 (10.0) 0 2 (10.0)
2 (10.0) 1 (5.0) 0 1 (5.0) 0 0 0 0
6 (30.0) 1 (5.0) 0 0 2 (10.0) 1 (5.0) 0 0
0 0 0 0 0 0 2 (11) 0
3 (16.7) 3 (16.7) 4 (22.2) 3 (16.7) 1 (5.6) 0 0 0
Data are n (%). an=20. bn=18. DCV, daclatasvir; EE/NGM, ethinyl estradiol and norgestimate.
substrates of CYP3A4 and have been demonstrated to increase exposure to a number of CYP3A4 substrates, including the calcineurin inhibitors cyclosporine and tacrolimus, when coadministered with telaprevir [11]. By contrast, coadministration of telaprevir and an EE/ norethindrone‑containing contraceptive results in a 26% reduction in EE Cmax, 28% reduction in EE AUC, and 33% reduction in EE Cmin, which may be due to telaprevir increasing first-pass metabolism of EE in the gastrointestinal tract by affecting transporters involved in the absorption of EE [31]. Similarly, boceprevir also reduces EE AUC by 24%, while increasing the Cmax and AUC of the synthetic progestin drospirenone by 99% and 57%, respectively, substantially increasing the risk of drospirenone-related AEs [10]. The drug–drug interactions observed between telaprevir and boceprevir and EE-based contraceptives necessitate the use of two nonhormonal methods of contraception during, and for telaprevir up to 2 weeks after, treatment. Ongoing clinical development of other direct-acting antivirals for HCV infection requires that their potential for drug interactions with concomitant medications is investigated. Antiviral Therapy 19.5
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Knowledge of their oral contraceptive interactions is vital given the known teratogenic and embryocidal potential of RBV and the likelihood that these newer agents will frequently be used in PEG‑IFN‑a/ RBV-containing combinations. Few studies specifically discuss what constitutes a subtherapeutic level of EE. However, most oral contraceptives typically contain EE at a dose of 30–35 µg, with low-dose contraceptives containing 20–25 µg of EE. Furthermore, it is not uncommon for upward dose titration to occur in the context of low-dose EE for breakthrough bleeding. Therefore, any drug–drug interactions resulting in EE levels less than those achieved with a 20 µg dose are likely to result in reduced efficacy, and potentially breakthrough bleeding [25]. In addition, it is generally accepted that even minor decreases (arbitrary definition ≤20% reduction in exposure; equivalent to a decrease from 30 µg to 20 µg of EE) in EE Cmax and AUCtau may result in a loss of contraceptive efficacy; therefore, where this occurs, patients are advised to use non-hormonal methods of contraception to prevent pregnancy [32]. 517
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The main objective of this study was to assess the effect of the investigational NS5A replication complex inhibitor DCV on the pharmacokinetics of EE and NGMN, the primary active components of a combined oral contraceptive, in healthy female subjects. Previously, DCV has demonstrated weak time-dependent inhibition of CYP3A4 in vitro, although subsequent in vitro work identified a low potential for CYP3A4 induction based on increased CYP3A4 messenger RNA activity in human hepatocytes (Bristol–Myers Squibb, unpublished data). Results from a clinical study assessing the impact of DCV on the pharmacokinetics of the CYP3A4 substrate midazolam demonstrated that DCV is unlikely to have a clinically significant impact on exposures to CYP3A4 substrates (Bristol–Myers Squibb, unpublished data). The potential for an interaction between DCV and substrates of sulfotransferase or UGTs has not been investigated. Unlike the reductions in EE exposure observed with concomitant telaprevir and boceprevir, in the current study only small increases (6–11% increase in GMR) in the Cmax of EE, NGMN and NG were observed with combined dosing of EE/NGM and DCV, and, similarly, modest increases (approximately 12%) in the AUCtau of NGMN and NG. All comparisons fell within the prespecified range for no effect (90% CIs for GMRs contained within the conventional bioequivalence range of 0.8–1.25), indicating that DCV does not have any clinically relevant effects on any active component of EE/NGM. In addition, coadministration of DCV with EE/NGM did not increase the frequency of metrorrhagia observed or change the individuals affected during cycle 3 compared with the administration of EE/NGM alone (cycles 1 and 2), suggesting maintenance of contraceptive efficacy of EE/NGM during DCV coadministration. Administration of DCV in combination with a combined oral contraceptive was also well tolerated in this study, with no serious or life-threatening AEs or AE-related discontinuations. Most AEs recorded were mild in intensity and were comparable to those observed during DCV monotherapy in HCV-infected patients [33]. Assessing the effect of anti-HCV drugs on the efficacy on oral contraceptives is a challenging undertaking. Most drug–drug interaction studies investigate only two drugs at a time to enable interpretation of any changes in pharmacokinetic parameters. However, assessing the effect of anti-HCV drugs, including DCV, individually does not reflect their real-world application as part of combination treatment regimens, when there may be multiple layers of enzyme induction or inhibition as well as other physiologic effects that may alter drug absorption or excretion. Indeed, future assessments looking at combination DAAs and oral contraceptive drug–drug interactions may be warranted to reflect the clinical 518
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use of these new agents. There are also disadvantages to conducting this, and other pharmacokinetic studies, in healthy HCV-negative subjects, who typically have lower BMIs and normal liver function compared with HCV-infected patients, which may have implications for drug metabolism and drug–drug interactions. In addition, most drug–drug interaction studies, including the current study, investigate only one type of oral contraceptive. Although the results from the current study suggest that DCV is unlikely to have any clinically meaningful effects on other EE-based oral contraceptives, it cannot be fully ascertained from the results presented herein that DCV will not have any effects on any other oral contraceptives that are currently available. In conclusion, the results of this study indicate that coadministration of DCV and an oral contraceptive containing EE and a progestin is well tolerated, does not result in clinically significant changes in exposure to either component, and hence, a loss of contraceptive efficacy due to a pharmacokinetic interaction is unlikely.
Acknowledgements Editorial assistance was provided by Kate Gaffey of Articulate Science (Manchester, UK) and was funded by Bristol–Myers Squibb. All authors wrote the manuscript. MB, DG and RB designed the research. MB, HS and CH analysed the data. HK and HJ contributed new reagents/ analytical tools.
Disclosure statement All authors are employees of Bristol–Myers Squibb.
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Accepted 26 November 2013; published online 17 December 2013
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