title: Drug Interactions with the Direct-Acting Antiviral Combination of Ombitasvir and Paritaprevir-Ritonavir.
abstract: The two direct-acting antiviral (2D) regimen of ombitasvir and paritaprevir (administered with low-dose ritonavir) is being developed for treatment of genotype subtype 1b and genotypes 2 and 4 chronic hepatitis C virus (HCV) infection. Drug-drug interactions were evaluated in healthy volunteers to develop dosing recommendations for HCV-infected subjects. Mechanism-based interactions were evaluated for ketoconazole, pravastatin, rosuvastatin, digoxin, warfarin, and omeprazole. Interactions were also evaluated for duloxetine, escitalopram, methadone, and buprenorphine-naloxone. Ratios of geometric means with 90% confidence intervals for the maximum plasma concentration and the area under the plasma concentration-time curve were estimated to assess the magnitude of the interactions. For most medications, coadministration with the 2D regimen resulted in a <50% change in exposures. Ketoconazole, digoxin, pravastatin, and rosuvastatin exposures increased by up to 105%, 58%, 76%, and 161%, respectively, and omeprazole exposures decreased by approximately 50%. Clinically meaningful changes in ombitasvir, paritaprevir, or ritonavir exposures were not observed. In summary, all 11 medications evaluated can be coadministered with the 2D regimen, with most medications requiring no dose adjustment. Ketoconazole, digoxin, pravastatin, and rosuvastatin require lower doses, and omeprazole may require a higher dose. No dose adjustment is required for the 2D regimen.
authors.affiliation: Department of Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., North Chicago, Illinois, USA prajakta.badri@abbvie.com.
authors.forename: Prajakta S
authors.initials: PS
authors.lastname: Badri
authors.affiliation: Department of Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Department of Clinical Pharmacology and Pharmacometrics-Biometrics, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Haoyu
authors.initials: H
authors.lastname: Wang
authors.affiliation: Infectious Disease Development, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Podsadecki
authors.affiliation: Department of Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Akshanth R
authors.initials: AR
authors.lastname: Polepally
authors.affiliation: Department of Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Khatri
authors.affiliation: Department of Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Jiuhong
authors.initials: J
authors.lastname: Zha
authors.affiliation: Department of Clinical Pharmacology and Pharmacometrics-Biometrics, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Chiu
authors.affiliation: Department of Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Walid M
authors.initials: WM
authors.lastname: Awni
authors.affiliation: Department of Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Rajeev M
authors.initials: RM
authors.lastname: Menon
mesh_terms: D000328:Adult; D000813:Anilides / Q000097:blood / Q000493:pharmacokinetics*; D000863:Antacids / Q000097:blood / Q000493:pharmacokinetics; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics; D000928:Antidepressive Agents / Q000097:blood / Q000493:pharmacokinetics; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics; D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002219:Carbamates / Q000097:blood / Q000493:pharmacokinetics*; D003521:Cyclopropanes; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009292:Narcotic Antagonists / Q000097:blood / Q000493:pharmacokinetics; D011392:Proline / Q000031:analogs & derivatives; D019438:Ritonavir / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides; D014633:Valine
chemical_list: D000813:Anilides; D000863:Antacids; D000889:Anti-Arrhythmia Agents; D000925:Anticoagulants; D000928:Antidepressive Agents; D000935:Antifungal Agents; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D009292:Narcotic Antagonists; D013449:Sulfonamides; C586094:ombitasvir; D011392:Proline; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir