Doravirine Can Be Co-Administered With Oral Contraceptives
Multiple dosing with doravirine does not change the plasma pharmacokinetics (PK) of a single dose of ethinyl estradiol (EE) or levonorgestrel (LNG) to a clinically important extent, according to data shown at the 6th International Workshop on HIV and Women.
Doravirine is a novel non-nucleoside reverse transcriptase inhibitor with an anticipated once daily dose of 100 mg. This drug is primarily metabolised by CYP3A4 but shows no inhibitory or inductive potential on CYP3A4-mediated metabolism in clinical studies. Doravirine has shown no interaction with the enzymes responsible for the metabolism of either EE or LNG.
Investigators from Merck conducted a study to assess the effect of doravirine on the plasma PK of an EE and LNG-containing oral contraceptive.
The study was an open-label, two-period, fixed-sequence design with a seven-day washout between Periods 1 and 2, conducted in HIV-negative women. In Period 1 participants received a single oral dose of 0.03 mg EE/0.15 mg LNG. In Period 2 they received 100 mg doravirine once daily for 17 days, with a single dose of EE/LNG co-administered with doravirine on day 14.
The study enrolled 20 post menopausal or oophorectomised women aged 42-65 years. Plasma samples were taken for up to 96 hours post dose in each period.
The investigators reported no serious adverse events (AEs) during the study. One participant discontinued due to a non-serious AE, not considered to be related to any study drug.
Twelve participants reported 27 post dose clinical AEs: three were considered to be associated with study drugs, two doravine (mild erythematous rash, oral herpes) and one both doravirine and EE/LNG (nervousness). One participant reported one laboratory AE associated with both doravirine and EE/LNG (red blood cells in urine). All AEs were transient and judged to be mild or moderate.
The geometric mean ratio (GMR) for EE, EE/LNG + doravirine: EE/LNG was: 0.98 (90% CI 0.94-1.03) for AUC0-inf and 0.83 (90% CI 0.80-0.87) for Cmax. GMR for LNG, EE/LNG + doravirine: 1.21 (90% CI 1.14-1.28) for AUC0-inf and 0.96 (90% CI 0.88-1.05) for Cmax.
Although the upper bound of the 90% CI for LNG AUC0-inf was outside the pre-specified bioequivalence interval (0.80-1.25), the investigators noted that the 90% CI for AUC0-last fell within the bounds: GMR 1.15 (90% CI 1.10-1.21). Although the upper bound of the 90% CI for LNG AUC0-inf slightly exceeded 1.25, this slight mean increase of 21% would not be expected to affect the efficacy of EE/LNG.
The investigators also reported that although bioequivalence criteria were met for Cmax of EE coadministered with doravirine, 8 out of 19 participants had individual GMR ratios below 0.80 -- they suggested that this was unlikely to have a clinically significant effect on the contraceptive efficacy of OC/LNG as this is dependent on the progesterone component of the combined pill. The investigators did not observe corresponding reduction in either AUC parameter.
As a result of this PK evaluation there are no restrictions in the use of oral contraceptives in the phase 3 trials of doravirine.
Anderson M et al. Effect of doravirine (MK-1439) on the pharmacokinetics of oral contraceptive (ethinyl estradiol [EE] and levonorgestrol [LNG]). 6th International Workshop on HIV & Women. 20-21 February 2016. Boston. Poster abstract 19.