title: Drug-Drug Interaction between the Direct-Acting Antiviral Regimen of Ombitasvir-Paritaprevir-Ritonavir plus Dasabuvir and the HIV Antiretroviral Agent Dolutegravir or Abacavir plus Lamivudine.
abstract: The direct-acting antiviral regimen of 25 mg ombitasvir-150 mg paritaprevir-100 mg ritonavir once daily (QD) plus 250 mg dasabuvir twice daily (BID) is approved for the treatment of hepatitis C virus genotype 1 infection, including patients coinfected with human immunodeficiency virus. This study was performed to evaluate the pharmacokinetic, safety, and tolerability effects of coadministering the regimen of 3 direct-acting antivirals with two antiretroviral therapies (dolutegravir or abacavir plus lamivudine). Healthy volunteers (n = 24) enrolled in this phase I, single-center, open-label, multiple-dose study received 50 mg dolutegravir QD for 7 days or 300 mg abacavir plus 300 mg lamivudine QD for 4 days, the 3-direct-acting-antiviral regimen for 14 days, followed by the 3-direct-acting-antiviral regimen with dolutegravir or abacavir plus lamivudine for 10 days. Pharmacokinetic parameters were calculated to compare combination therapy with 3-direct-acting-antiviral or antiretroviral therapy alone, and safety/tolerability were assessed throughout the study. Coadministration of the 3-direct-acting-antiviral regimen increased the geometric mean maximum plasma concentration (Cmax) and the area under the curve (AUC) of dolutegravir by 22% (central value ratio [90% confidence intervals], 1.219 [1.153, 1.288]) and 38% (1.380 [1.295, 1.469]), respectively. Abacavir geometric mean Cmax and AUC values decreased by 13% (0.873 [0.777, 0.979]) and 6% (0.943 [0.901, 0.986]), while those for lamivudine decreased by 22% (0.778 [0.719, 0.842]) and 12% (0.876 [0.821, 0.934]). For the 3-direct-acting-antiviral regimen, geometric mean Cmax and AUC during coadministration were within 18% of measurements made during administration of the 3-direct-acting-antiviral regimen alone, although trough concentrations for paritaprevir were 34% (0.664 [0.585, 0.754]) and 27% (0.729 [0.627, 0.847]) lower with dolutegravir and abacavir-lamivudine, respectively. All study treatments were generally well tolerated, with no evidence of increased rates of adverse events during combination administration. These data indicate that the 3-direct-acting-antiviral regimen can be administered with dolutegravir or abacavir plus lamivudine without dose adjustment.
authors: Division of Clinical Pharmacokinetics and Pharmacodynamics, AbbVie Inc., North Chicago, Illinois, USA.
authors: Amit
authors: A
authors: Khatri
authors: Division of Antiviral Development, AbbVie Inc., North Chicago, Illinois, USA.
authors: Roger
authors: R
authors: Trinh
authors: Division of Clinical Pharmacokinetics and Pharmacodynamics, AbbVie Inc., North Chicago, Illinois, USA.
authors: Weihan
authors: W
authors: Zhao
authors: Division of Antiviral Development, AbbVie Inc., North Chicago, Illinois, USA.
authors: Thomas
authors: T
authors: Podsadecki
authors: Division of Clinical Pharmacokinetics and Pharmacodynamics, AbbVie Inc., North Chicago, Illinois, USA rajeev.menon@abbvie.com.
authors: Rajeev
authors: R
authors: Menon
mesh_terms: D015081:2-Naphthylamine; D000328:Adult; D000813:Anilides / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D044966:Anti-Retroviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology; D003521:Cyclopropanes; D015224:Dideoxynucleosides / Q000493:pharmacokinetics / Q000494:pharmacology; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D019698:Hepatitis C, Chronic / Q000188:drug therapy; D006575:Heterocyclic Compounds, 3-Ring / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D047029:Lactams, Macrocyclic; D019259:Lamivudine / Q000493:pharmacokinetics / Q000494:pharmacology; D047028:Macrocyclic Compounds / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011392:Proline / Q000031:analogs & derivatives; D011728:Pyridones; D019438:Ritonavir / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014498:Uracil / Q000031:analogs & derivatives / Q000494:pharmacology; D014633:Valine; D000099226:Dolutegravir; D000099227:Abacavir
chemical_list: D015081:2-Naphthylamine; D000813:Anilides; D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D015224:Dideoxynucleosides; D004338:Drug Combinations; D006575:Heterocyclic Compounds, 3-Ring; D047029:Lactams, Macrocyclic; D019259:Lamivudine; D047028:Macrocyclic Compounds; D010078:Oxazines; D010879:Piperazines; D011392:Proline; D011728:Pyridones; D019438:Ritonavir; D013449:Sulfonamides; D014498:Uracil; D014633:Valine; D000099226:Dolutegravir; C492871:abacavir, lamivudine drug combination; D000099227:Abacavir; C586094:ombitasvir; C588260:dasabuvir; C585405:paritaprevir