Open AccessA 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
Author(s) -
Ankrom Wendy,
Jackson Rudd Deanne,
Zhang Saijuan,
Fillgrove Kerry L.,
Gravesande Kezia N.,
Matthews Randolph P.,
Brimhall Darin,
Stoch S. Aubrey,
Iwamoto Marian N.
Publication year - 2021
Publication title -
journal of the international aids society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.724
H-Index - 62
ISSN - 1758-2652
DOI - 10.1002/jia2.25858
Subject(s) - levonorgestrel , medicine , tolerability , pharmacokinetics , adverse effect , cmax , population , ethinylestradiol , pharmacology , family planning , environmental health , research methodology
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.