Abstract Body

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.