title: Drug-Drug Interactions between Sofosbuvir and Ombitasvir-Paritaprevir-Ritonavir with or without Dasabuvir.
abstract: 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 ombitasvir-paritaprevir-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.).
authors.affiliation: AbbVie Inc., Clinical Pharmacology and Pharmacometrics, North Chicago, Illinois, USA jennifer.king@abbvie.com.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: King
authors.affiliation: AbbVie Inc., Clinical Pharmacology and Pharmacometrics, North Chicago, Illinois, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dutta
authors.affiliation: AbbVie Inc., Infectious Disease Development, North Chicago, Illinois, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cohen
authors.affiliation: AbbVie Inc., Infectious Disease Development, North Chicago, Illinois, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Podsadecki
authors.affiliation: AbbVie Inc., Biometrics, North Chicago, Illinois, USA.
authors.forename: Bifeng
authors.initials: B
authors.lastname: Ding
authors.affiliation: AbbVie Inc., Clinical Pharmacology and Pharmacometrics, North Chicago, Illinois, USA.
authors.forename: Walid M
authors.initials: WM
authors.lastname: Awni
authors.affiliation: AbbVie Inc., Clinical Pharmacology and Pharmacometrics, North Chicago, Illinois, USA.
authors.forename: Rajeev M
authors.initials: RM
authors.lastname: Menon
mesh_terms: D015081:2-Naphthylamine; D000328:Adult; D000813:Anilides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002219:Carbamates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003521:Cyclopropanes; D004347:Drug Interactions / Q000502:physiology*; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D011392:Proline / Q000031:analogs & derivatives; D019438:Ritonavir / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000069474:Sofosbuvir / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014498:Uracil / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014633:Valine
chemical_list: D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir; D000069474:Sofosbuvir