Background: Fostemsavir is a prodrug of temsavir, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+ T cells. Women of child-bearing potential represent a significant proportion of the heavily-treatment experienced HIV-infected population; effective and convenient contraception is important. This study assessed the impact of fostemsavir on the pharmacokinetics (PK) of a combined OC containing EE and NE (Loestrin 1.5/30; 1.5 mg NE, 30 µg EE).
Methods: AI438019 was a Phase 1, open-label, single-sequence, 4-cycle, 4-treatment study in 26 healthy female subjects. Serial blood samples for PK up to 24 hours post-dose and single samples for serum progesterone were collected. Plasma concentrations were quantified by validated LC/MS/MS methods. Geometric mean ratios (GMRs) and 90% confidence intervals (CI) were derived for EE and NE PK using linear mixed-effects models. Adverse events (AEs) were monitored throughout the study.

Cycle 1Cycle 2Cycle 3Cycle 4
Days 1-8Days 1-28Days 1-28Days 1-21
Day 1 = 21st day of existing OC once daily (QD) (Treatment A)Existing OC QD Days 1-21 (Treatment B)Loestrin 1.5/30 QD Days 1-21 (Treatment C)Loestrin 1.5/30 QD Days 1-11 Loestrin 1.5/30 QD + fostemsavir 600 mg BID Days 12 - 21 (Treatment D)
serial PK collection Day 1serial PK collection Day 21serial PK collection Day 10 and 21serial PK collection Day 21
serum progesterone Day 1serum progesterone Day 21serum progesterone Day 11, 15 and 21serum progesterone Day 11, 15 and 21
[Study Design]

Results: Only comparisons of EE and NE PK between Treatment D and Treatment C are presented. Fostemsavir coadministration increased EE exposures ~40%. The 90% CIs for NE Cmax and AUC(TAU) GMRs were within 0.80-1.25. Serum progesterone levels suggested fostemsavir did not negatively impact suppression of ovulation. Most study drug-related AEs were mild; 1 subject (3.8%) reported a moderate AE of headache (Treatment D).

ParameterTreatment C Day 21 Adjusted Geometric MeanTreatment D Day 21 Adjusted Geometric MeanGMR (90% CI) Treatment D vs. C
EE Cmax (pg/mL)1081501.39 (1.28, 1.51)
EE AUC(TAU) (pg.h/mL)108315141.40 (1.29, 1.51)
NE Cmax (pg/mL)23629255821.08 (1.01, 1.16)
NE AUC(TAU) (pg.h/mL)1702931843021.08 (1.03, 1.14)
[EE/NE Cmax and AUC(TAU)]

Conclusions: Fostemsavir, in the absence of a pharmacoenhancer, may be coadministered with combined oral contraceptives containing NE and a reduced dose of EE.

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