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1 Drug Interactions with the Direct-Acting Antiviral Combination of Ombitasvir and 2 Paritaprevir PDF

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AAC Accepted Manuscript Posted Online 12 October 2015 Antimicrob. Agents Chemother. doi:10.1128/AAC.01778-15 Copyright © 2015 Badri et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. 1 Title 2 Drug Interactions with the Direct-Acting Antiviral Combination of Ombitasvir and 3 Paritaprevir/Ritonavir (2D Regimen) 4 D o w 5 Prajakta S. Badri1#, Sandeep Dutta1, Haoyu Wang2, Thomas J. Podsadecki3, Akshanth R. n lo a 6 Polepally1, Amit Khatri1, Jiuhong Zha1, Yi-Lin Chiu2, Walid M. Awni1, Rajeev M. d e d 7 Menon1 fr o m h 8 1Department of Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., North tt p : / 9 Chicago, IL, USA; 2Department of Clinical Pharmacology and Pharmacometrics - /a a c 10 Biometrics, AbbVie, Inc., North Chicago, IL, USA; 3Infectious Disease Development, .a s m 11 AbbVie, Inc., North Chicago, IL, USA .o r g / o 12 Running Head: Ombitasvir/paritaprevir/ritonavir drug interactions n A p r 13 # Address correspondence to Prajakta S. Badri, PhD ([email protected]) il 2 , 2 0 1 9 b y g u e s t 1 14 Abstract 15 The 2D regimen of ombitasvir and paritaprevir (administered with low-dose ritonavir) is 16 being developed for treatment of genotype subtype 1b and genotypes 2 and 4 chronic 17 hepatitis C virus (HCV) infection. Drug-drug interactions were evaluated in healthy D o w 18 volunteers to develop dosing recommendations for HCV-infected subjects. Mechanism- n lo 19 based interactions were evaluated for ketoconazole, pravastatin, rosuvastatin, digoxin, a d e d 20 warfarin, and omeprazole. Interactions were also evaluated for duloxetine, escitalopram, f r o m 21 methadone, and buprenorphine/naloxone. Ratios of geometric means with 90% h t t 22 confidence intervals for maximum plasma concentration and area under the plasma p : / / a 23 concentration-time curve were estimated to assess the magnitude of interaction. For most a c . a 24 medications, coadministration with the 2D regimen resulted in a < 50% change in s m . o 25 exposures. Ketoconazole, digoxin, pravastatin, and rosuvastatin exposures increased by r g / o 26 up to 105%, 58%, 76%, and 161%, respectively, and omeprazole exposures decreased by n A 27 approximately 50%. Clinically meaningful changes in ombitasvir, paritaprevir, or p r il 2 28 ritonavir exposures were not observed. In summary, all 11 evaluated medications can be , 2 0 29 coadministered with the 2D regimen, with most medications requiring no dose 1 9 b 30 adjustment. Ketoconazole, digoxin, pravastatin, and rosuvastatin require lower doses and y g u 31 omeprazole may require a higher dose. No dose adjustment is required for the 2D e s t 32 regimen. 2 33 Introduction 34 Treatment outcomes for patients with chronic HCV infection have improved considerably 35 in recent years due to the development of direct-acting antiviral agents (DAAs) that target 36 various steps in the HCV lifecycle (1,2). These agents produce higher response rates and D o 37 have fewer toxicities compared with previous interferon-based therapies. w n lo a 38 Ombitasvir, a potent NS5A inhibitor, and paritaprevir, a potent NS3/4A protease inhibitor d e d 39 identified for clinical development by AbbVie and Enanta, both show in vitro antiviral fr o m 40 activity against HCV subtypes 1a, 1b, 2a, 3a, 4a, and 6a (3-5). Paritaprevir is h t t p 41 administered with low-dose (100 mg) ritonavir to increase paritaprevir peak and trough : / / a a 42 concentrations and overall drug exposure (6). The all oral, interferon-free 2D regimen of c . a s 43 ombitasvir and paritaprevir/ritonavir with or without ribavirin has been evaluated in m . o r 44 clinical studies in patients with HCV genotypes 1b, 2, 3 and 4 infection (7-9). The 2D g / o 45 regimen has been approved in the European Union (EU) for the treatment of chronic HCV n A p 46 genotype 4 infection, including those with compensated cirrhosis. The 3D regimen of r il 2 , 47 ombitasvir, paritaprevir/ritonavir, and dasabuvir has been approved with ribavirin for the 2 0 1 48 treatment of chronic HCV genotype 1a and without ribavirin for the treatment of chronic 9 b y 49 HCV 1b infection in the United States and the EU (10-12). In addition, the 2D regimen is g u e 50 being developed in Japan for the treatment of HCV subtype 1b and genotype 2 infection s t 51 (8). Dasabuvir is not active against genotypes other than genotype 1 (10,12); therefore, it 52 is not part of the 2D regimen, which is intended to be used in other genotypes. 3 53 The in vitro metabolic profile of the 2D regimen (13) indicates paritaprevir and ritonavir 54 are primarily metabolized by cytochrome P450 (CYP) 3A and ombitasvir is 55 predominantly metabolized by amide hydrolysis followed by oxidative metabolism. 56 Ritonavir is a CYP3A inhibitor, whereas the DAAs do not inhibit CYP enzymes. In vitro 57 data also suggest that at clinically relevant concentrations, paritaprevir is an organic anion D o w 58 transporting polypeptide (OATP) 1B1/B3 inhibitor, and paritaprevir and ritonavir are n lo a 59 potential inhibitors of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). d e d 60 The DAAs and ritonavir are in vitro substrates of P-gp. Paritaprevir is also a substrate of f r o m 61 BCRP and OATP1B1/B3. h t t p : / 62 A broad drug-drug interaction program was conducted in healthy volunteers to evaluate /a a c 63 the potential for drug interactions with this 2D regimen. These studies characterized .a s m 64 mechanism-based (i.e., enzyme- or transporter-related) interactions using probe substrates . o r g 65 and inhibitors based on regulatory guidances (14,15), and interactions that may occur with / o n 66 commonly used medications in HCV-infected patients (13,16,17). Results from these A p r 67 studies were used to develop dosing recommendations for patients treated with the 2D il 2 , 2 68 regimen. 0 1 9 b y 69 Subjects and Methods g u e s t 70 Study designs. Eight open-label, Phase 1 clinical studies were conducted in healthy 71 volunteers in accordance with Good Clinical Practice guidelines and ethical principles that 72 have their origin in the Declaration of Helsinki. The studies were performed among 4 4 73 clinical study sites in the United States and Canada between July 2012 and September 74 2013. The study protocols and amendments were approved by the institutional review 75 boards and written informed consent was obtained from each subject before any study- 76 related procedures were performed. These studies included multiple treatment arms and 77 results from arms that received the 3D regimen of ombitasvir, paritaprevir/ritonavir, and D o w 78 dasabuvir have been reported previously (18). Results from treatment arms that received n lo a 79 the 2D regimen are the primary focus of this report. d e d f r 80 Inhibitors of metabolic enzymes and drug transporters were not allowed within one month o m h 81 of enrollment. Subjects enrolled in the methadone and buprenorphine/naloxone studies t t p : / 82 had been taking stable doses of methadone or buprenorphine/naloxone for a minimum of /a a c 83 14 days before the screening visit. Subjects with clinically significant renal disease were .a s m 84 excluded from participation in all studies. . o r g / o 85 Drug-drug interactions were evaluated for the 2D regimen of ombitasvir (25 mg) and n A p 86 paritaprevir/ritonavir (150/100 mg) using 11 medications from several different drug r il 2 87 classes (Table 1). Key aspects of the study designs are presented in Figure 1. Most , 2 0 1 88 evaluations were conducted under once daily, multiple dosing conditions, although a few 9 b y 89 mechanism-based interactions were evaluated under single dosing conditions. For all g u e 90 evaluations, ombitasvir and paritaprevir/ritonavir were coadministered with the interacting s t 91 medications after consumption of a moderate-fat meal (approximately 1,900 to 2,300 92 calories/day with 40% of calories from fat). 5 93 Safety and tolerability. The safety and tolerability of the 2D regimen and the interacting 94 medications were assessed based on adverse event monitoring, physical examinations, 95 laboratory tests, vital signs, and electrocardiogram assessments. 96 Pharmacokinetic evaluations. Intensive pharmacokinetic sampling was performed as D 97 noted in Figure 1 for determination of plasma concentrations of paritaprevir, ritonavir, o w n 98 ombitasvir, and the interacting medications and their metabolites, if applicable. Plasma lo a d e 99 concentrations were determined using validated liquid chromatography with tandem mass d f r 100 spectrometric detection methods. The lower limits of quantitation (LLOQs) for o m h 101 paritaprevir, ritonavir, and ombitasvir were 0.6 ng/mL (inter-run accuracy [% bias] –1.0% t t p : / 102 to 4.5%; inter-run precision [% CV] 5.0% to 7.0%), 4.9 ng/mL (% bias –4.3% /a a c 103 to -0.1%; %CV 2.8% to 4.2%), and 0.5 ng/mL (% bias 0.7% to 4.7%; %CV 3.8% to .a s m 104 5.3%), respectively. The LLOQs for the concomitant medications were 0.01 ng/mL for . o r g 105 digoxin (% bias –3.99% to 2.05%; %CV 3.71% to 9.64%), 0.02 ng/mL for naloxone / o n 106 (%bias –2.8% to –0.9%; %CV 1.9% to 3.5%), 0.05 ng/mL for S-desmethylcitalopram A p r 107 (% bias –5.01% to 3.24%; %CV 2.97% to 11.71%), 0.1 ng/mL for buprenorphine il 2 , 2 108 (% bias -3.7% to 0.0%; %CV 2.4% to 3.2%), norbuprenorphine (% bias –3.0% 0 1 9 109 to -1.1%; %CV 2.7% to 4.6%), and rosuvastatin (% bias -0.281% to 1.76%; %CV 0.915% b y g 110 to 3.87%), 100 ng/mL for ketoconazole (% bias –2.75% to –0.796%; %CV 1.83% to u e s t 111 3.54%), 0.2 ng/mL for escitalopram (% bias –3.94% to 3.12%; %CV 3.36% to 5.53%), 112 0.5 ng/mL for duloxetine (% bias –4.19 to 3.87%; %CV 2.81% to 6.06%) and pravastatin 113 (% bias –1.63% to 1.53%; %CV 3.99% to 7.80%), 1 ng/mL for R-methadone (% bias 6 114 0.4% to 3.3%; %CV 1.6% to 3.1%), S-methadone (% bias 1.1% to 3.2%; %CV 2.1% to 115 3.2%), and omeprazole (% bias –0.9% to 4.4%; %CV 4.7% to 9.7%), and 5 ng/mL for 116 R-warfarin (% bias –6.74% to 0.473%; %CV 4.17% to 5.42%) and S-warfarin (% 117 bias -6.78% to 1.38%; %CV 3.83% to 5.90%). For digoxin, urine was also collected and 118 the excreted fraction of drug was measured (LLOQ of 2 ng/mL; % bias –7.80% D o w 119 to -0.63%; %CV 4.99% to 18.22%). n lo a d 120 Pharmacokinetic analyses were performed by noncompartmental methods using Phoenix® e d f r 121 WinNonlin® Version 6.0 or above (Pharsight, A Certara® Company, St. Louis, MO). The o m h 122 main pharmacokinetic parameters of interest were the maximum observed plasma t t p : / 123 concentration (Cmax) and the area under the plasma concentration-time curve (AUC) /a a c 124 during a dosing interval (AUC ) or from time zero to infinity (AUC for a single dose). .a 24 ∞ s m 125 Additional pharmacokinetic parameters of interest included the time to C (T ), . max max o r g 126 24 hour concentration (C24), and terminal phase elimination half-life (t1/2). o/ n A p 127 Pharmacodynamic evaluations. Pharmacodynamic measurements were performed to r il 2 128 monitor for signs of withdrawal that could have been caused by changes in methadone , 2 0 1 129 and buprenorphine/naloxone exposures during coadministration with the 2D regimen. 9 b y 130 Pupil diameter and two self-administered instruments (short opiate withdrawal scale score g u e 131 and the desire for drugs questionnaire) were measured before and during s t 132 coadministration. 7 133 Statistical analyses. Statistical analyses were conducted using SAS®, Version 9.2 (SAS 134 Institute, Inc., Cary, NC). Effects of ombitasvir and paritaprevir/ritonavir on the 135 interacting medications and vice versa were estimated by analyzing log-transformed C e max 136 and AUC values under a repeated measures analysis framework. Geometric mean ratios 137 (GMRs) and 90% confidence intervals (CIs) for C and AUC were calculated to D max o w 138 quantify the magnitude of drug interactions. n lo a d e 139 Results d f r o m 140 Subject demographics. A total of 119 subjects received at least one dose of the 2D h t t p 141 regimen and/or interacting medication in these studies, 76% of whom were male. The : / / a a 142 demographics of subjects across the studies were similar: the age of subjects ranged from c . a s 143 20 to 55 years, mean age ranged from 30.3 to 39.1 years, and median body weight ranged m . o r 144 from 72.5 to 80.0 kg. Across the arms receiving the 2D regimen, 60.5% of subjects were g / o 145 white, 34.5% were black, 2.5% were Asian, and 2.5% were other races. n A p r 146 Pharmacokinetics il 2 , 2 0 1 147 Mechanism-Based Drug-Drug Interactions 9 b y g 148 Results from studies of mechanism-based interactions of substrates and inhibitors of u e s 149 CYPs and substrates of drug transporters on ombitasvir, paritaprevir, and ritonavir t 150 exposures are shown in Figure 2, and effects of ombitasvir and paritaprevir/ritonavir on 151 the substrates and inhibitors are shown in Figure 3. The pharmacokinetic parameters for 8 152 ombitasvir, paritaprevir, ritonavir, and the substrates and inhibitors are presented in Table 153 2. The magnitude of each drug interaction is discussed below. 154 CYP3A and P-gp inhibitor (ketoconazole). When ketoconazole was coadministered 155 with the 2D regimen, ketoconazole C was not affected (10% increase), but max D 156 ketoconazole AUC increased by 105%. The mean t of ketoconazole was almost 4-fold o 1/2 w n 157 longer (16.0 versus 4.3 h) in the presence of ombitasvir and paritaprevir/ritonavir. lo a d e 158 Increased C and AUC values were also observed for paritaprevir (72% and 116%, max d f r 159 respectively) and ritonavir (27% and 51%, respectively). Ombitasvir C was not o max m h 160 affected (2% decrease), but AUC increased by 26%. The mean t1/2 of paritaprevir was tt p : / 161 more than 2-fold longer (14.4 versus 6.2 h) and the mean t1/2 of ombitasvir increased from /a a c 162 24.9 to 39.5 h. .a s m . o 163 CYP2C9 substrate (warfarin). Coadministration of warfarin with the 2D regimen did r g / o 164 not affect R- or S-warfarin exposures (≤ 15% change in Cmax and AUC values) or n A p 165 ombitasvir, paritaprevir, or ritonavir exposures (≤ 15% change in Cmax and AUC values). r il 2 , 2 166 CYP2C19 substrate (omeprazole). In the presence of the 2D regimen, the Cmax and 0 1 9 167 AUC values of omeprazole were reduced by 52% and 54%. Paritaprevir, ritonavir, and b y g 168 ombitasvir exposures were relatively unchanged (≤ 7% change in Cmax and AUC values) u e s 169 by coadministration with omeprazole. t 170 P-gp substrate (digoxin). When digoxin was coadministered with the 2D regimen, 171 values for digoxin C , AUC, and C increased by 58%, 36%, and 24%, respectively. max 24 9 172 There was no change in the fraction of unchanged drug eliminated in the urine (ratio of 173 fraction excreted: 1.01). Ombitasvir, paritaprevir, and ritonavir exposures were not 174 affected by coadministration with digoxin (≤ 15% change in C and AUC values). max 175 OATP1B1/B3 substrate (pravastatin). Coadministration of pravastatin with the 2D D 176 regimen increased pravastatin C and AUC values by 43% and 76%, respectively. o max w n 177 Coadministration increased paritaprevir C and AUC values by 44% and 33%, increased lo max a d e 178 ritonavir C and AUC values by 37% each, but had no effect on ombitasvir C or max max d f r 179 AUC (≤ 6% decrease). o m h t t 180 OATP1B1/B3 and BCRP substrate (rosuvastatin). Rosuvastatin exposures increased p : / / a 181 in the presence of the 2D regimen: C increased by 161% and AUC increased by 33%. a max c . a 182 Paritaprevir C and AUC increased by 40% and 22%, respectively, but ritonavir and s max m . o 183 ombitasvir exposures were minimally affected (≤ 12% change in C and AUC values). r max g / o n 184 Interactions with Commonly Used Medications A p r il 2 185 Effects of the 2D regimen on exposures of medications commonly used in HCV-infected , 2 0 186 patients are presented in Figure 3, and effects of these commonly used medications on the 1 9 b 187 exposures of ombitasvir, paritaprevir, and ritonavir are presented in Figure 2. The y g u 188 pharmacokinetic parameters for the DAAs, ritonavir, and the medications are presented in e s t 189 Table 2. 10

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volunteers in accordance with Good Clinical Practice guidelines and ethical The study protocols and amendments were approved by the institutional review. 74 paritaprevir/ritonavir (150/100 mg) using 11 medications from several laboratory tests, vital signs, and electrocardiogram assessments.
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