A semi-mechanistic pharmacokinetic model for depot medroxyprogesterone acetate and drug-drug interactions with antiretroviral and antituberculosis treatment.

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Depot medroxyprogesterone acetate (DMPA) is an injectable hormonal contraceptive, widely used by women of childbearing potential living with HIV and/or tuberculosis. As medroxyprogesterone acetate (MPA) is a CYP3A4 substrate, drug-drug interactions (DDIs) with antiretroviral or antituberculosis treatment may lead to subtherapeutic MPA concentrations (<0.1 ng/mL), resulting in contraception failure, when DMPA is dosed at 12-week intervals. A pooled population pharmacokinetic analysis with 744 plasma MPA concentrations from 138 women treated with DMPA and antiretroviral/antituberculosis treatment across three clinical trials was performed. Monte Carlo simulations were performed to predict the percentage of participants with subtherapeutic MPA concentrations and to derive alternative dosing strategies. MPA clearance increased by 24.7% with efavirenz co-administration. Efavirenz plus antituberculosis treatment (rifampicin+isoniazid) increased clearance by 52.4%. Conversely, lopinavir/ritonavir and nelfinavir decreased clearance (28.7% and 15.8%, respectively), but lopinavir/ritonavir also accelerated MPA’s appearance into the systemic circulation, thus shortening the terminal half-life. A higher risk of subtherapeutic MPA concentrations at week 12 was predicted on a typical 60-kg woman on efavirenz (4.99%) and efavirenz with antituberculosis treatment (6.08%) when compared to MPA alone (2.91%). This risk increased in women with higher body weight. Simulations show that re-dosing every 8-10 weeks circumvents the risk of subtherapeutic MPA exposure associated with these DDIs. Dosing DMPA every 8-10 weeks should eliminate the risk of subtherapeutic MPA exposure caused by co-administered efavirenz and/or antituberculosis treatment, thus reducing the risk of contraceptive failure.

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Authors: Jose Francis, Rosie Mngqibisa, Helen McIlleron, Michelle A Kendall, Xingye Wu, Kelly E Dooley, Cynthia Firnhaber, Catherine Godfrey, Susan E Cohn, Paolo Denti, A5093, A5283, A5338 study teams