A phase 1, open-label study to evaluate the drug interaction between islatravir (MK-8591) and the oral contraceptive levonorgestrel/ethinyl estradiol in healthy adult females

Abstract

Introduction: Hormonal contraceptives are among the most effective forms of reversible contraception, but many other compounds, including some antiretrovirals, have clinically meaningful drug-drug interactions (DDIs) with hormonal contraceptives. Islatravir is a novel human immunodeficiency virus nucleoside reverse transcriptase translocation inhibitor currently in clinical development for treatment and prevention of HIV infection. A phase 1 clinical trial was conducted to evaluate the DDI of islatravir and the combination of oral contraceptive levonorgestrel (LNG)/ethinyl estradiol (EE).

Methods: This was an open-label, two-period, fixed-sequence, DDI clinical trial in healthy, postmenopausal or bilaterally oophorectomized females aged 18 through 65 years in the United States between October 2016 and January 2017. A single dose of LNG 0.15 mg/EE 0.03 mg was given followed by a 7-day washout. Islatravir, 20 mg, was then dosed once weekly for 3 weeks; a single dose of LNG 0.15 mg/EE 0.03 mg was given concomitantly with the third dose of islatravir. Pharmacokinetic samples for plasma LNG and EE concentrations were collected pre-dose and up to 120 hours post-dose in each period. Safety and tolerability were assessed throughout the trial by clinical assessments, laboratory evaluations and examination of adverse events.

Results and discussion: Fourteen participants were enrolled. The pharmacokinetics of LNG and EE were not meaningfully altered by co-administration with islatravir. For the comparison of (islatravir + LNG/EE)/(LNG/EE alone), the geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for LNG AUC_0-inf and C_max were 1.13 (1.06, 1.20) and 0.965 (0.881, 1.06), respectively. For EE, the GMRs (90% CI) for AUC_0-inf and C_max were 1.05 (0.981, 1.11) and 1.02 (0.971, 1.08), respectively. Co-administration of all three drugs was generally well tolerated.

Conclusions: The results of this trial support the use of LNG/EE contraceptives in combination with islatravir without dose adjustment.

Keywords: antiretrovirals; drug-drug interaction; hormonal contraceptive; islatravir; levonorgestrel/ethinyl estradiol.

Figure 1

(a) Mean linear (± SD) plasma concentration of LNG versus time following administration of a single dose of LNG/EE (0.15/0.03 mg) with or without co‐administration of multiple weekly doses of 20 mg ISL. (b) Mean linear (± SD) plasma concentration of EE versus time following administration of a single dose of LNG/EE (0.15/0.03 mg) with or without co‐administration of multiple weekly doses of 20 mg ISL. (c) Individual and geometric mean ratios and 90% CI of LNG AUC_0–∞ and C _max. (d) Individual and geometric mean ratios and 90% CI of EE AUC_0–∞ and C _max. Abbreviations: EE, ethinyl estradiol; GMR, geometric mean ratio; ISL, islatravir; LNG, levonorgestrel.