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GLECAPREVIR AND PIBRENTASVIR INTERACTIONS WITH COMBINATION ANTIRETROVIRAL REGIMENS
Matthew P. Kosloski1, Sandeep Dutta1, Rolando M. Viani1, Xin Qi1, Roger Trinh1, Andrew Campbell1, Wei Liu1
1AbbVie, North Chicago, IL, USA
The direct acting antiviral combination of glecaprevir (GLE; formerly ABT-493), a NS3/4 protease inhibitor discovered by AbbVie and Enanta, and pibrentasvir (PIB; formerly ABT-530), a NS5A inhibitor, is being developed to treat chronic hepatitis C virus (HCV) genotype 1 to 6 infection. Current guidelines recommend that HCV/HIV co-infected patients be treated the same as HCV mono-infected patients, with considerations for potential drug-drug interactions (DDI) with antiretrovirals. Elvitegravir (ELV)/cobicistat (COBI)/ emtricitabine (FTC)/tenofovir alafenamide (TAF) or abacavir (ABC)/dolutegravir (DTG)/ lamivudine (3TC) are recommended combination antiretroviral regimens . A Phase 1 DDI study was conducted to evaluate pharmacokinetics, tolerability, and safety of GLE + PIB coadministered with ELV/COBI/FTC/TAF or DTG/ABC/3TC.
An open label, multiple-dose study was conducted in healthy adult subjects receiving GLE 300 mg QD + PIB 120 mg QD with ELV/COBI/FTC/ TAF 150/150/200/10 mg QD (n=24, Arm 1) or ABC/DTG/3TC 600/50/300 mg QD (Arm 2, N=24) alone or in combination. Intensive pharmacokinetic assessments were performed for GLE, PIB, and anti-retroviral drugs on multiple days. Effects of GLE + PIB on the pharmacokinetics of the antiretroviral drugs and vice versa were assessed by a repeated-measures analysis using SAS. Safety was evaluated via assessment of adverse events, vital signs, ECGs and clinical laboratory tests.
In Arm 1, Cmax and AUC were increased by 150% to 205% for GLE and by 24% to 57% for PIB, when co-administered with ELV/COBI/FTC/TAF. GLE + PIB increased Cmax and AUC of ELV and COBI by 29% to 47%, but not of FTC or tenofovir (≤ 12% change). In Arm 2, GLE and PIB Cmax and AUC were slightly lower (25% to 28%) when coadministered with ABC/DTG/3TC. Cmax and AUC of ABC, DTG, and 3TC were not impacted by GLE + PIB (≤ 13% difference). No clinically significant vital signs or laboratory measurements were observed during the study with the exception of one subject in Arm 1 who discontinued from the study due to a Grade 3 decrease in neutrophil count during ELV/COBI/FTC/ TAF and GLE-PIB coadministration.
Results from the study supported coadministration of GLE/PIB with these combination antiretroviral regimens in ongoing Phase 3 studies in HIV/HCV co-infected subjects. No dose-adjustment is required when GLE/PIB are coadministered with ELV, FTC, TAF, ABC, DTG, or 3TC.