551. MK-8591 Does Not Alter the Pharmacokinetics of the Oral Contraceptives Ethinyl Estradiol and Levonorgestrel

Abstract

BackgroundOver 2 million girls and young women are living with HIV, being newly infected at disproportionately high rates. HIV infection adds risks to pregnancy, including vertical transmission and maternal death. Hormonal contraceptives are among the most effective reversible contraceptives, but they have clinically meaningful drug–drug interactions (DDI) with many antiretrovirals (ARV). MK-8591 is a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) currently in Phase 2 clinical development for treatment of HIV. Unlike many ARVs, MK-8591 is not an inhibitor or inducer of major CYP enzymes and is not expected to alter the pharmacokinetics (PK) of hormonal contraceptives. This clinical study evaluated the DDI of MK-8591 with levonorgestrel (LNG) and ethinyl estradiol (EE) to support use of hormonal contraceptives with MK-8591.MethodsThis was an open-label, two-period, fixed-sequence DDI study in 14 healthy, postmenopausal or oopherectomized females aged 50–64. A single dose of LNG 0.15 mg/EE 0.03 mg was given followed by a 7-day washout. MK-8591 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 MK-8591. PK samples were collected for evaluation of LNG and EE levels. Individual values of AUC0-inf and Cmax were natural log-transformed prior to analysis and evaluated separately using a linear mixed effects model with a fixed effects term for treatment. An unstructured covariance matrix was used to allow for unequal treatment variances and to model the correlation between the treatment measurements within each subject.ResultsThe PK of EE and LNG were not meaningfully altered by co-administration with MK-8591. For the comparison of (MK-8591 + LNG/EE) / (LNG/EE alone), the geometric mean ratios (GMRs) (90% confidence intervals (CIs)) for LNG AUC0-inf and Cmax were 1.13 (1.06, 1.20) and 0.965 (0.881, 1.06), respectively. For EE the GMRs (90% CI) for AUC0-inf and Cmax 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.ConclusionThe results of this study support use of hormonal contraceptives in HIV-infected patients receiving MK-8591.Disclosures W. Ankrom, Merck & Co, Inc.: Employee and Shareholder, Salary. D. Jonathan, Merck: Employee, Salary. D. Rudd, Merck & Co., INC.: Employee, Salary. S. Zhang, Merck & Co, Inc.: Employee, Salary. K. Fillgrove, Merck & Co., Inc.: Employee, Salary. K. Gravesande, Kezia Gravesande: Research Contractor, Salary. R. Matthews, Merck: Employee, Salary. A. Stoch, Merck & Co, Inc.: Employee and Shareholder, Salary. M. Iwamoto, Merck & Co, Inc.: Employee and Shareholder, Salary.

Islatravir Is Not Expected to Be a Victim or Perpetrator of Drug-Drug Interactions via Major Drug-Metabolizing Enzymes or Transporters

“…Another PK and safety study demonstrated no meaningful drug–drug interactions between islatravir and tenofovir disoproxil fumarate, which is eliminated renally via OAT1 and OAT3, and dolutegravir, which is hepatically metabolized by UGT enzymes and CYP3A4 [ 70 , 71 , 76 ]. No significant drug–drug interactions have been observed following co-administration of islatravir with levonorgestrel/ethinyl estradiol [ 77 ], common components of hormonal contraceptives that are extensively metabolized by CYP3A4, are glucuronidated, and undergo biliary and urinary excretion [ 78 ].…”

“…This finding is of particular clinical relevance for PLWH who may require polypharmacy for the management of both HIV and common comorbidities, such as diabetes, cardiovascular disease, and depression. Islatravir is not expected to interact with the major pathways associated with other antiretroviral agents, including dolutegravir, doravirine, and tenofovir disoproxil fumarate [ 54 , 71 , 76 ] as well as with commonly prescribed medications, including metformin, omeprazole, clopidogrel, statins, alprazolam, buprenorphine/naloxone, selective serotonin reuptake inhibitors, oral contraceptives, and rifampin [ 77 ]. These results support the continued clinical evaluation of islatravir as an option across diverse populations for the treatment and prevention of HIV-1 infection.…”

Safety and Pharmacokinetics of Once-Daily Multiple-Dose Administration of Islatravir in Adults Without HIV

“…10 Adenosine deaminase is the only known contributor to islatravir metabolism, 11 and islatravir is not expected to have significant drug-drug interactions. [12][13][14] In addition, food had little impact on islatravir PK. 10 The long intracellular half-life and high potency of ISL-TP allow for a variety of islatravir dosing options, ranging from once daily (QD) to less frequent dosing schedules.…”

Lack of a Clinically Meaningful Drug Interaction Between the HIV‐1 Antiretroviral Agents Islatravir, Dolutegravir, and Tenofovir Disoproxil Fumarate

“…29 Furthermore, no significant drug-drug interactions have been observed following coadministration of islatravir with levonorgestrel and/or ethinyl estradiol, common components of hormonal contraceptives. 35 A potential limitation of this trial is that only a single dose of islatravir was administered during each treatment period. However, given what is known about islatravir, dolutegravir, and tenofovir, islatravir is not anticipated to affect the pharmacokinetics of either drug regardless of dose or number of doses.…”

“… 29 Furthermore, no significant drug‐drug interactions have been observed following coadministration of islatravir with levonorgestrel and/or ethinyl estradiol, common components of hormonal contraceptives. 35 …”