Lack of clinically significant drug–drug interactions between the third‐generation integrase strand transfer inhibitor VH4524184 (VH‐184) and combined oral contraceptives

17 Background: Long-acting antiretroviral therapy offers people with HIV-1 more convenient and sustainable treatment options, improving quality of life and adherence. VH4524184 (VH-184) is a third-generation integrase strand transfer inhibitor (INSTI) that has potent antiviral activity, long-acting potential and an enhanced in vitro resistance profile compared with second-generation INSTIs. Since VH-184 may be administered concomitantly with combined oral contraceptives (COCs), it is important to understand any clinically relevant drug–drug interactions. In this study, we assessed the impact of VH-184 on the pharmacokinetics (PK) of a common COC containing ethinyl estradiol (EE) and norethindrone acetate (NEA). Material and Methods: We conducted a phase 1, open-label, single-sequence, 1-way study in female participants without HIV aged 18 to 45 years. Participants received once-daily oral EE 30 μg/NEA 1.5 mg alone (treatment period 1; Days 1–10) or with once-daily oral VH-184200 mg (treatment period 2; Days 11–20) after a 21-day run-in period of EE/NEA followed by a 7-day washout period. The primary endpoint was maximum plasma concentration (Cmax) and area under the concentration-time curve from time 0 to the end of the dosing interval (AUC₀-τ) for EE and NEA. Secondary endpoints included VH-184 PK parameters, safety and tolerability. Results: Of the 26 participants enrolled, 20 completed the study. Five participants discontinued before treatment Period 1, and one participant withdrew after completing treatment Period 2 but before the follow-up visit. Geometric least squares mean ratios (90% CI) with vs. without VH-184 of Cmax and AUC₀-τ were 1.041 (0.974–1.112) and 1.107 (1.062–1.153) for EE, respectively, and 1.210 (1.133–1.293) and 1.234 (1.194–1.274) for NEA, respectively. Steady-state VH-184 concentrations were achieved in ~10 days, consistent with prior studies. Overall, 12 (46%) participants reported 16 treatment-emergent adverse events (TEAEs). The only TEAEs reported by >1 participant were headache (n = 3), abdominal pain (n = 2), fatigue (n = 2) and positive SARS-CoV-2 test (n = 2). All TEAEs had a maximum intensity of Grade 1. Five (19%) participants reported six drug-related TEAEs, none of which were reported by >1 participant. The four drug-related TEAEs reported during treatment period 2 were labelled events for EE/NEA and/or INSTIs. No TEAEs led to discontinuation during either treatment period. No serious AEs or deaths were reported. Five participants experienced asymptomatic Grade 1 or 2 transaminase elevations after treatment period 2 (Day 21). There were no clinically relevant changes in other laboratory parameters, electrocardiograms or vital signs. Conclusions: VH-184 had no effect on the steady-state PK of EE after repeat oral administration with a common COC containing EE/NEA. A slight increase in NEA exposure was observed with VH-184 coadministration, which was not considered clinically significant. EE/NEA did not meaningfully affect the steady-state PK of VH-184. VH-184 combined with EE/NEA was well tolerated in female participants without HIV. These results indicate that VH-184 can be administered with COCs containing EE/NEA without impacting the efficacy of COCs or the PK of VH-184.