Levonorgestrel (LNG) is primarily metabolized by CYP3A4. Efavirenz (EFV) and rifampin (RIF) induce, while isoniazid (INH) inhibits CYP3A4. ACTG A5375, a pharmacokinetic (PK) trial of LNG emergency contraception (EC), showed that double-dose LNG (3mg vs 1.5mg) offsets the effects of EFV and RIF on LNG PK over the first 8 hours after a single dose for EC. We characterized the pharmacogenetics of these drug interactions.
A5375 enrolled participants in Africa, Asia, South America and the US into four groups: women living with HIV (WLH) on EFV-based ART were randomized 1:2 to LNG 1.5mg (Group A) or 3mg (Group B); WLH on dolutegravir (DTG)-based ART were assigned to 1.5mg (Group C; control group); Women treated for TB with INH/RIF were assigned to 3mg (Group D). On day 0, women received a single dose of LNG EC. Intensive PK sampling was done pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 and 48 hours post-dose. AUC0-8h was the primary outcome. Genotyping defined CYP2B6 metabolizer and NAT2 acetylator status (associated with plasma EFV and INH exposure, respectively). Linear regression models adjusted for BMI and age, and used log-transformed PK parameters.
Of 122 cisgender women, 118 (97%) were evaluable for genetic associations: 73 (62%) identified as Black, 33 (28%) Asian, and 10 (8%) Latina. In the combined EFV Groups A/B, 8 (15%) of 52 were CYP2B6 poor metabolizers. In Group D, 15 (44%) of 34 were NAT2 slow acetylators. Within Groups A/B, CYP2B6 genotypes that increase plasma EFV exposure had more rapid LNG clearance (β=0.29, p=0.025). In CYP2B6 poor metabolizers in Group B, LNG AUC0-8h was lower than Group C (GMR=0.60; 90% CI 0.44, 0.82; Figure); LNG Cmax was not significantly lower (GMR=0.77; 90% CI 0.55, 1.06). Within Group D, NAT2 genotypes that increase plasma INH exposure had slower LNG clearance (β=-0.31, p=0.022). In NAT2 slow acetylators in Group D, LNG AUC0-8h was greater than Group C (GMR=1.36; 90% CI 1.08, 1.71; Figure). BMI was independently associated with LNG AUC0-8h in each analysis.
Pharmacogenetics of ART and TB drugs affect interactions with LNG EC. CYP2B6 slow metabolizer genotypes worsen the EFV-LNG interaction, likely by increased CYP3A induction with higher EFV exposure, making this interaction more difficult to overcome. NAT2 slow acetylator genotypes attenuate the RIF-LNG interaction, likely by increased CYP3A inhibition with higher INH exposure.
Relationships between genetics and plasma LNG exposure.