CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

Methods: This was an open-label, 2-period, fixed-sequence study in healthy adult subjects. In Period 1 (P1), a single dose of doravirine 50 mg was administered on Day 1. In Period 2 (P2), following a 7-day washout, RTV 100 mg was administered twice daily for 20 days and co-administered with doravirine 50 mg the morning of Day 14. Blood samples to measure doravirine concentrations were collected through 120 and 168 hours post doravirine dose in P1 and P2, respectively. Results: Eight adult male subjects were enrolled and completed the study. Following co-administration with multiple-doses of RTV, doravirine AUC, Cmax, and C24hr increased. The geometric mean (GM) ratios (90% confidence intervals) [(doravirine +RTV)/doravirine] for doravirine AUC0-∞, Cmax, and C24hr were 3.54 (3.04, 4.11), 1.31 (1.17, 1.46), and 2.91 (2.33, 3.62), respectively. The apparent GM (GCV%) half-life (hr) of doravirine was increased when co administered with RTV, 13.97 (10.59%) and 35.16 (12.27%), respectively. The median (range) Tmax (hr) values following a single dose of doravirine alone and when co administered with RTV were 3.50 (2.00, 5.00) and 5.00 (1.00, 16.00), respectively. Eight subjects reported a total of 22 adverse events (AEs); all AEs, with the exception of one headache of moderate intensity, were mild. There were no serious AEs and no discontinuations due to an AE. Conclusion: Consistent with the metabolic profile of doravirine, co-administration of doravirine with the CYP3A inhibitor RTV significantly increased doravirine AUC0-∞ and C24hr, with a more modest increase in Cmax, via CYP3A inhibition. Doravirine was generally well tolerated when administered alone or with RTV. 413 GLECAPREVIR AND PIBRENTASVIR INTERACTIONS WITH COMBINATION ANTIRETROVIRAL REGIMENS Matthew P. Kosloski , Sandeep Dutta, Rolando M. Viani, Xin Qi, Roger Trinh, Andrew Campbell, Wei Liu AbbVie, North Chicago, IL, USA Background: 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. Methods: 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. Results: 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. Conclusion: 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. 414 EFFECT OF LOW-DOSE METHOTREXATE ON THE PHARMACOKINETICS OF TENOFOVIR David Gingich 1 , Heather Ribaudo 2 , Amy Kantor 2 , James H. Stein 3 , Judith S. Currier 4 , Priscilla Hsue 1 , Francesca Aweeka 1 1 Univ of California San Francisco, San Francisco, CA, USA, 2 Harvard Univ, Boston, MA, USA, 3 Univ of Wisconsin, Madison, WI, USA, 4 Univ of California Los Angeles, Los Angeles, CA, USA Background: HIV infected individuals have increased risk of premature cardiovascular disease in spite of effective antiretroviral therapy (ART). Low dose methotrexate (LDMTX) is being evaluated to counter HIV-associated inflammation (ACTG 5314). Methotrexate and tenofovir (TFV) are both eliminated by the kidneys, so a pharmacokinetic (PK) substudy investigated whether LDMTX alters TFV PK. Methods: In the parent trial, participants were randomized LDMTX or placebo weekly for 24 wks with close monitoring for viral load (VL) and CD4 count. Eligible PK sub-study participants were on stable TFV containing ART. Intensive PK sampling occurred at wk 2, at the time of the 2nd dose of either LDMTX 10 mg or placebo which was dosed with TFV. Serial PK sampling was at 0, 0.5, 1, 2, 4 and 6 hrs post-dosing with a subgroup having extended sampling at 8, 12 and 24 hrs. PK parameters were the area under the concentration time curve (AUC0-6hr and AUC0-24hr) and peak concentration (Cmax). The study had 95% power to detect a 40% increase in AUC with a relaxed type-one error rate (1-sided 5%). Analyses were conducted on natural log scale. Statistical tests (two sample t-tests) are 2-sided and interpreted at the 10% level consistent with the study design. Results: 48 participants had PK sampling (20 LDMTX, 28 placebo); all were taking TFV in the form of tenofovir disoproxil fumarate. Participants were 92%male, 48%white and 46% black; characteristics were balanced across treatment arms with the exception of concomitant PI-use (25% LDMTX, 43% placebo). For TFV, there was a 22% reduction in the geometric mean (GM) AUC0-6hr in the context of LDMTX; a similar reduction was apparent for AUC0-24hr and Cmax (Table). Analysis by concomitant protease inhibitor (PI) use, suggested a greater difference in the absence of a PI that appeared driven by 5 participants in the LDMTX armwith low TFV concentrations over the sampling period. A formal interaction test was not significant (P>0.3). For PK of LDMTX, the AUC0-6hr and Cmax are summarized descriptively (Table). A5314 follow-up is ongoing; interim safety analyses of VL have raised no concerns. Conclusion: During TFV and LDMTX co-administration, decreases in the TFV AUC0-24hr and Cmax are apparent. These decreases appear driven by a subset of participants in the LDMTX armwho were not on PI’s. The results suggest alterations in TFV dosing during co-treatment with LDMTX are likely unnecessary for patients on PI. Further study of an interaction in patients not on PIs is warranted.

Poster and Themed Discussion Abstracts

CROI 2017 170