Drug-drug interaction profile of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir

Menon, Rajeev; Badri, Prajakta; Wang, Tianli; Polepally, Akshanth R.; Zha, Jiuhong; Khatri, Amit; Wang, Haoyu; Hu, Beibei; Coakley, Eoin; Podsadecki, Thomas; Awni, Walid M.; Dutta, Sandeep

doi:10.1016/j.jhep.2015.01.026

Cited by 119 publications

(178 citation statements)

References 15 publications

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“…Cytochrome P450 (CYP450) 3A4 isoenzyme is primarily responsible for the metabolism of paritaprevir, ritonavir, and to a lesser extent dasabuvir, which is primarily metabolized by CYP2C8 (10,11). Ombitasvir is metabolized by amide hydrolysis.…”

Section: Discussionmentioning

confidence: 99%

Drug-Drug Interactions between Sofosbuvir and Ombitasvir-Paritaprevir-Ritonavir with or without Dasabuvir

King

Dutta

Cohen

et al. 2016

Antimicrob Agents Chemother

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The combination of ombitasvir (an NS5A inhibitor), paritaprevir (an NS3/4A inhibitor) coadministered with ritonavir (r), and dasabuvir (an NS5B nonnucleoside polymerase inhibitor), referred to as the 3D regimen, and the combination of ombitasvirparitaprevir-r, referred to as the 2D regimen, have demonstrated high efficacy with and without ribavirin in hepatitis C virus (HCV)-infected subjects. These regimens have potential for coadministration with sofosbuvir (nucleoside NS5B inhibitor) in the treatment of HCV. This phase 1, drug-drug interaction, open-label, multiple-dose study enrolled 32 healthy subjects to receive the 3D or 2D regimen in combination with sofosbuvir. Doses of study drugs were as follows: ombitasvir-paritaprevir-r, 25/150/ 100 mg daily (QD); dasabuvir, 250 mg twice daily (BID); and sofosbuvir, 400 mg QD. Blood samples were collected on study days 7, 14, and 21 for evaluating drug interaction at steady state. The effect of the 3D and 2D regimens on the pharmacokinetics of sofosbuvir and its circulating metabolite GS-331007 and vice versa was assessed by a repeated-measures analysis. Exposures of the 3D and 2D regimens were similar (<20% change) during coadministration with sofosbuvir and during administration alone. Sofosbuvir exposures were 61% to 112% higher with the 3D regimen and 64% to 93% higher with the 2D regimen than with sofosbuvir alone. GS-331007 total exposures were 27% and 32% higher with the 3D and 2D regimens, respectively, than with sofosbuvir alone. Increases in sofosbuvir and GS-331007 exposures likely resulted from breast cancer resistance protein (BCRP) and/or P glycoprotein (P-gp) transporter inhibition by paritaprevir and ritonavir. No subjects discontinued the study due to study drug-related adverse events. No dose adjustment is recommended for 3D, 2D, or sofosbuvir in clinical trials exploring the safety and efficacy of the combination. (This study has been registered at ClinicalTrials.gov under registration no. NCT02356562 and NCT02292719.)A combination of three direct-acting antivirals (DAA) (3D regimen) with or without ribavirin has been approved by the U.S. Food and Drug Administration and the European Medicines Agency, among other regulatory agencies, for the treatment of patients with chronic HCV genotype 1 (GT1) infection, including those with compensated cirrhosis (1, 2). The 3D regimen consists of paritaprevir, a nonstructural 3/4A (NS3/4A) protease inhibitor identified as a lead compound by AbbVie and Enanta, coadministered with ritonavir (r), administered once daily (paritaprevirr); ombitasvir, a NS5A inhibitor, administered once daily; and dasabuvir, a nonnucleoside NS5B RNA polymerase inhibitor, administered twice daily. The two-DAA combination regimen (2D regimen) consisting of paritaprevir-r, ombitasvir, and ribavirin has shown potent antiviral activity in vitro against HCV GT1a, -1b, -2a, -2b, -3A, -4a, and -6a. Thus, several clinical studies have evaluated the 2D regimen with or without ribavirin in patients with HCV genotype 1b, 2, 3, and 4 infections ...

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Section: Discussionmentioning

confidence: 99%

Drug-Drug Interactions between Sofosbuvir and Ombitasvir-Paritaprevir-Ritonavir with or without Dasabuvir

King

Dutta

Cohen

et al. 2016

Antimicrob Agents Chemother

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“…More specific information on the influence of concomitant medications can be gained from formal drugdrug interaction studies, a number of which have been conducted with agents representing different enzyme or transporter substrates and inhibitor/inducer classes. Descriptions of these study results have recently been published (19,(21)(22)(23) and can be used as a guide for dosing of concomitant medications with the 3D regimen.…”

Section: Discussionmentioning

confidence: 99%

“…Components of the 3D regimen are substrates or inhibitors for a number of metabolic enzymes and transport proteins, including various CYP family members, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1/B3), and uridine diphosphate glucuronosyltransferase (UGT) 1A1 (19). Co-medication use was defined as receipt for ≥6 weeks (approximately half the treatment duration [12 weeks] of a typical HCV DAA regimen) during the treatment period.…”

Section: Pharmacokinetic Model Development and Statistical Analysesmentioning

confidence: 99%

Population Pharmacokinetics of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin in Patients with Hepatitis C Virus Genotype 1 Infection: Combined Analysis from 9 Phase 1b/2 Studies

Mensing

Polepally

König

et al. 2015

AAPS J

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Abstract. Direct-acting antiviral agents (DAAs) are established as the standard of care for chronic hepatitis C virus (HCV) infection. One of the newest additions to the HCV arsenal is an oral three-DAA combination therapy (i.e., the 3D regimen) that does not require concomitant use of pegylated interferon. The clinical development program for the 3D regimen has yielded a robust dataset that is inclusive of various dosing schemes and a diverse patient population. Using data from nine phase 1b/2a/ 2b studies that enrolled patients with HCV genotype 1 infection, population pharmacokinetic models were developed for each component of the 3D regimen (ombitasvir, paritaprevir, ritonavir, and dasabuvir) and for ribavirin, an adjunctive therapy used to enhance therapeutic efficacy in some populations. Formulation effects, accumulation, relative bioavailability, and interactions between DAAs were assessed during model development, and demographic and clinical covariates were identified and evaluated for their effects on drug exposures. Proposed models were assessed via goodness-of-fit plots, visual predictive checks, and bootstrap evaluations. Population pharmacokinetic models adequately described their respective plasma concentration-time data with precise and reliable model parameter estimates and with good predictive performance. Covariates, including age, sex, body weight, cytochrome P450 2C8 inhibitor use, non-Hispanic ethnicity, and creatinine clearance, were associated with apparent clearance and/or apparent volume parameters; however, the magnitude of effect on drug exposure was modest and not considered to be clinically significant. No patient-related or clinical parameters were identified that would necessitate dose adjustment of the 3D regimen in patients with HCV genotype 1 infection.

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“…The latter pharmacokinetic profile subjects them to multiple drug-drug interactions via CYP3A system, particularly paritaprevir and ritonavir. [29] Because non-renal mechanisms accounted for the elimination of all-oral regimen, renal impairment may not require specific recommendation. On the other hand, due to dependence on hepatic elimination, all-oral regimen is not recommended for patients with moderate hepatic impairment and is contraindicated in those with severe hepatic impairment.…”

Section: Sofosbuvirmentioning

confidence: 99%

Direct acting anti-hepatitis C virus drugs: Clinical pharmacology and future direction

Geddawy

Ibrahim

Elbahie

et al. 2017

Journal of Translational Internal Medicine

130

102

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Chronic hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The introduction of direct acting antiviral agents (DAAs) for its treatment represents a major advance in terms of sustained virologic response (SVR) rates and adverse effect profiles. Mechanistically, DAAs inhibit specific HCV non-structural proteins (NS) that are vital for its replication. Boceprevir, telaprevir, simeprevir, asunaprevir, grazoprevir and paritaprevir are NS3/4A inhibitors. Ombitasvir, ledipasvir, daclatasvir, elbasvir and velpatasvir are NS5A inhibitors. Sofosbuvir and dasabuvir are NS5B inhibitors. Currently, a combination of two or more DAAs is the corner stone for the treatment of HCV infection. However, the success of DAA therapy is facing several challenges, including the potential of drug-drug interactions and resistant variance. Moreover, the shortage of relevant clinical pharmacological data and drug interaction regarding DAA is a clinical concern. The present review discusses the clinical pharmacology of DAAs with special emphasis on drug-drug interaction.

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Drug-drug interaction profile of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir

Cited by 119 publications

References 15 publications

Drug-Drug Interactions between Sofosbuvir and Ombitasvir-Paritaprevir-Ritonavir with or without Dasabuvir

Drug-Drug Interactions between Sofosbuvir and Ombitasvir-Paritaprevir-Ritonavir with or without Dasabuvir

Population Pharmacokinetics of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin in Patients with Hepatitis C Virus Genotype 1 Infection: Combined Analysis from 9 Phase 1b/2 Studies

Direct acting anti-hepatitis C virus drugs: Clinical pharmacology and future direction

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