Effect of double-dose levonorgestrel subdermal implant in women taking efavirenz-based antiretroviral therapy: The DoubLNG pharmacokinetic study

by Selleckchem | Mar 06 2023

Objective: We evaluated the pharmacokinetics of double-dose levonorgestrel implants to overcome the drug-drug interaction with efavirenz-based antiretroviral therapy (ART).

Study design: We conducted a non-randomized, open-label, parallel-group, longitudinal pharmacokinetic study among Ugandan women ages 18 to 45 years. Participants with HIV on ART containing efavirenz 600mg received 300mg LNG implants (Jadelle®, Bayer, New Zealand): 300LNG+ART group. We compared our outcomes with women without HIV using standard dose, 150mg LNG implants: 150LNG group. The implant was placed on day 0 in both groups, and we quantified plasma LNG concentrations over 48 weeks post-implant insertion. LNG pharmacokinetic parameters were estimated using noncompartmental techniques. Our primary outcome was the geometric mean ratio (GMR) with 90% confidence intervals (CI) of LNG area under the concentration-time curve over 24 weeks (AUC0-24w) between groups. Demographic data were described as median (interquartile range). A secondary outcome compared between-group percent of levonorgestrel concentrations ≥300 pg/mL, a minimum threshold selected a priori based on observed pregnancies in Ugandan women on standard-dose levonorgestrel implants plus efavirenz.

Results: We enrolled 27 women in the 300LNG+ART group [34 (28.0-40.5) years and 61.0 (49.8-66.0) kg] and 19 women in the 150LNG group [33 (30.0-34.5) years and 64.9 (59.0-74.5) kg]. LNG AUC0-24w was 34% lower for 300LNG+ART vs. 150LNG: [geometric mean 9998 vs. 15,231 pg⁎week/mL, respectively (GMR 0.66 (90% CI: 0.54-0.80)]. The percentage of participants with LNG concentrations ≥300 pg/mL was not statistically different between groups at week 24 (300LNG+ART: 74.1%; 150LNG: 89.5%; P=0.27).

Conclusion: Double-dose LNG implant did not completely overcome the drug-drug interaction with efavirenz.

Implication: In women using antiretroviral therapy (ART) containing efavirenz, placing two implant systems (300mg) did not normalize LNG pharmacokinetics compared with the standard-dose implant (150mg), and some women had evidence of ovulatory activity. Alternative ART without drug-drug interactions, such as dolutegravir, are recommended with contraceptive implants.

Comments：

The study evaluated the pharmacokinetics of double-dose levonorgestrel (LNG) implants in Ugandan women with HIV on efavirenz-based antiretroviral therapy (ART). The study found that the double-dose LNG implant did not completely overcome the drug-drug interaction with efavirenz, as the LNG area under the concentration-time curve over 24 weeks was 34% lower in the 300LNG+ART group compared to the 150LNG group. The percentage of participants with LNG concentrations ≥300 pg/mL was not statistically different between groups at week 24. The study suggests that alternative ART without drug-drug interactions, such as dolutegravir, should be used with contraceptive implants in women with HIV.