Pharmacokinetics of dose-adjusted levonorgestrel emergency contraception combined with efavirenz-based antiretroviral therapy or rifampicin-containing tuberculosis regimens

Abstract

Objectives: To determine if double-dose levonorgestrel emergency contraception (EC) in combination with efavirenz or rifampicin, 2 drugs known to decrease levonorgestrel exposure, resulted in similar pharmacokinetics compared to standard-dose levonorgestrel EC without drug-drug interactions.

Study design: We conducted a phase 2, open-label, multicenter, partially randomized, 4 parallel group trial in pre-menopausal females ≥16 years old without an indication for EC and not on hormonal contraception. Participants on dolutegravir-based antiretroviral therapy (ART) received levonorgestrel 1.5 mg (control group); those on rifampicin-containing tuberculosis therapy received levonorgestrel 3 mg; those on efavirenz-based ART were randomized 1:2 to levonorgestrel 1.5 mg or 3 mg. Plasma was collected through 48 hours post-dose to assess levonorgestrel pharmacokinetics. Area under the concentration-time curve (AUC) over 8 hours was the primary outcome. Levonorgestrel pharmacokinetic parameters were compared between groups using geometric mean ratios (GMR) with 90% confidence intervals.

Results: The median (Q1, Q3) age for all participants (n = 118) was 34 (27, 41) years and BMI was 23.2 (20, 26.3) kg/m². Participants receiving levonorgestrel 1.5mg plus efavirenz (n = 17) had 50% lower AUC_0-8h compared to the control group (n = 32) [0.50 (0.40, 0.62)]. Participants receiving levonorgestrel 3 mg had a similar AUC_0-8h when receiving either efavirenz (n = 35) [0.99 (0.81, 1.20)] or rifampicin (n = 34) [1.16 (0.99, 1.36)] compared to control. Levonorgestrel 3 mg resulted in similar or higher maximum concentration with either efavirenz [1.17 (0.96, 1.41)] or rifampicin [1.27 (1.09, 1.49)] compared to the control group.

Conclusions: Doubling the dose of levonorgestrel EC successfully increased levonorgestrel exposure over the first 8 hours in participants receiving either efavirenz-based ART or rifampicin-containing tuberculosis therapy.

Implications: Adjusting levonorgestrel emergency contraception from 1.5 mg to 3 mg improves levonorgestrel pharmacokinetic exposure in participants receiving either efavirenz-based antiretroviral regimens or rifampicin-containing tuberculosis therapy. These data support guideline recommendations to double the dose of levonorgestrel emergency contraception in persons on medications that decrease levonorgestrel exposure by inducing levonorgestrel metabolism.

Keywords: Drug interaction; Efavirenz; Emergency contraception; Pharmacokinetics; Rifampicin.

Figure 1.. Participant disposition.

Primary PK analysis set includes all participants included in the analysis. PK sensitivity analysis set excludes participants with suboptimal dolutegravir, efavirenz, or rifampicin concentrations. Abbreviations: ART, antiretroviral therapy; DTG, dolutegravir; EFV, efavirenz; LNG, levonorgestrel; PK, pharmacokinetic; RIF, rifampicin.

Figure 2.. Levonorgestrel concentration-time curve (median, 25% and 75% quartile) in plasma over 48 hours after a single dose of emergency contraception.

Figure 2a illustrates the control group (solid line, triangle) compared to efavirenz-levonorgestrel 1.5mg group (dotted-line, squares). Figure 2b illustrates the efavirenz-levonorgestrel 1.5mg group (dotted-line, squares) and the efavirenz-levonorgestrel 3mg group (dashed line, circles). Figure 2c illustrates the control group (solid line, triangle) compared to the efavirenz-levonorgestrel 3mg group (dashed line, circles). Figure 2d illustrates control group (solid line, triangle) compared to the rifampicin group (dashed line, squares). The control group participants were on dolutegravir-based ART and received levonorgestrel 1.5mg. The efavirenz-levonorgestrel 1.5mg group participants were on efavirenz-based ART and received levonorgestrel 1.5mg. The efavirenz-levonorgestrel 3mg group participants were on efavirenz-based ART and received levonorgestrel 3mg. The rifampicin group participants were on rifampicin-containing tuberculosis therapy in the continuation phase and received levonorgestrel 3mg. Levonorgestrel was administered as a single dose with food at time 0.