Abstract Body

Expanding access to contraception is essential to prevent pregnancy-related health risks for women with TB. Levonorgestrel (LNG) for emergency contraception (EC) is metabolized via cytochrome P450 (CYP) 3A4 and rifampicin (RIF), a potent CYP3A4 inducer, reduces LNG exposure by 57%. Obesity also decreases LNG exposure by 50%. Some guidelines recommend doubling the LNG EC dose when taken with CYP3A4 inducers, but this has not been evaluated in clinical studies with RIF. We hypothesized that doubling the LNG EC dose during RIF therapy would result in similar PK exposure compared to standard dose LNG in the absence of a drug-drug interaction (DDI).

ACTG A5375 was a multicenter, parallel group, PK trial of pre-menopausal females, ?16 years old, without an indication for EC at entry. Participants without HIV taking RIF on continuation phase of TB therapy received LNG 3mg (n=34) and were compared to participants with HIV on DTG-based ART who received LNG 1.5mg (n=32; control group). Plasma was collected prior to a single dose of LNG, then 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48h post-dose. LNG concentrations were measured by LC-MS/MS and PK parameters calculated by non-compartmental methods. Appropriateness of the DTG as the control group was confirmed by comparison to historical LNG PK data. PK parameters were compared between groups by geometric mean ratio (GMR; 90% CI) adjusted for baseline BMI. Participants were followed for 4 weeks to assess adverse events (AE).

All participants (n=66) self-identified as cis-women, 54 (82%) Black, 6 (9%) Latina, and 4 (6%) Asian and enrolled between May 2019 and Nov 2020. BMI was lower in the RIF group compared to the control group, [mean (SD): 22.4 (4.9) vs 26.1 (7.1) kg/m2, p=0.01]. Table 1 summarizes LNG PK parameters. LNG AUCs over 8 and 24 hours were similar between groups. The Cmax was 27% higher while the T1/2 was 57% shorter in the RIF group, resulting in 82% lower Clast and 21% lower AUC48h compared to the control group. Three participants (2 RIF group; 1 DTG group) reported Grade 2/3 LNG-related AEs (nausea and menstrual symptoms)

Dose adjustment of LNG EC from 1.5mg to 3mg in those on RIF-based TB therapy resulted in similar or higher LNG exposure over the first 24 hours compared to the control group. RIF therapy shortened the LNG half-life, resulting in lower exposure after 48 hours. Since Cmax is associated with EC effectiveness, these data support dose-adjustment of LNG EC to 3mg in those taking RIF.