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.

Role of islatravir in HIV treatment and prevention: an update

“…Furthermore, a phase 1b study analyzed the impact of ISL on the pharmacokinetic profile of the NNRTI doravirine in adults without HIV infection [40] and found that the pharmacokinetic of doravirine administered alone and in combination with ISL were comparable and that doravirine did not have a meaningful impact on the pharmacokinetic of ISL. Similarly, a study of 14 healthy subjects found no clinically meaningful interaction between ISL and the investigational NNRTI MK-8507 [41]. Additionally, ISL had no clinically significant interaction when combined with dolutegravir and TDF [42].…”

Personalizing prevention: Advances in pharmacotherapy for HIV prevention

“…A subdermal implant, islatravir (MK-8591), is novel HIV nucleoside reverse transcriptase translocation inhibitor (NRTTI), making it the first-in-class translocation inhibitor. 52 It has high TA B L E 3 Summary of select investigational products for HIV pre-exposure prophylaxis. ARV potency, a unique mechanism of action, and a prolonged plasma half-life of 48-64 h, making it an ideal option for treatment and prevention.…”

“…Implants, films, and vaginal rings provide additional novel delivery options for HIV prevention. A subdermal implant, islatravir (MK‐8591), is novel HIV nucleoside reverse transcriptase translocation inhibitor (NRTTI), making it the first‐in‐class translocation inhibitor 52 . It has high ARV potency, a unique mechanism of action, and a prolonged plasma half‐life of 48–64 h, making it an ideal option for treatment and prevention.…”

Contraception and Abortion Care for People Living With HIV: A Clinical Guide for Reproductive Health Practitioners

“…Likewise, an earlier prospective, nonrandomized trial suggested that norethisterone‐based progestin‐only contraceptives exhibit increased drug levels when co‐administered with ritonavir‐boosted protease inhibitors 60 . However, not all ART medications demonstrate alterations in contraceptive hormone pharmacokinetics: a recent phase 1 trial found that the pharmacokinetics of COCs (levonorgestrel/ethinyl estradiol) were not altered with islatravir (a novel NRTI) and did not require dose adjustment 61 …”

“…60 However, not all ART medications demonstrate alterations in contraceptive hormone pharmacokinetics: a recent phase 1 trial found that the pharmacokinetics of COCs (levonorgestrel/ethinyl estradiol) were not altered with islatravir (a novel NRTI) and did not require dose adjustment. 61 Another drug-drug interaction of clinical concern is hyperkalemia when drospirenone-containing contraceptives are used along with cobicistat-containing ART regimens. 58 Currently, drospirenone-containing contraceptives are generally contraindicated in users of cobicistat-boosted protease inhibitors when an alternative or additional contraceptive method is available.…”