A Semimechanistic Pharmacokinetic Model for Depot Medroxyprogesterone Acetate and Drug–Drug Interactions With Antiretroviral and Antituberculosis Treatment

Abstract

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 12week 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% Accepted ArticleThis article is protected by copyright. All rights reserved 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. Main text

Pharmacogenetics of interaction between depot medroxyprogesterone acetate and efavirenz, rifampicin, and isoniazid during treatment of HIV and tuberculosis

“…A population pharmacokinetic model was developed to describe the concentrations on MPA using nonlinear mixed effects modelling in the software NONMEM applying first-order conditional estimation algorithm with eta-epsilon interaction [37]. The detailed description of the model is provided elsewhere [15,38]. Briefly, MPA pharmacokinetics was modelled using a one-compartment disposition model with first-order elimination.…”

Pharmacokinetics and Drug-Drug Interactions of Abacavir and Lamuvudine Co-administered With Antituberculosis Drugs in HIV-Positive Children Treated for Multidrug-Resistant Tuberculosis

“…This means that they were replaced with half the lower limit of quantitation (LLOQ), except for consecutive values in a series, for which the trailing BLQ values were ignored for the fit but included in the diagnostic plots. The additive error was inflated by half the LLOQ value for the imputed BLQ values (i.e., by LLOQ/2) to allow for extra uncertainty due to the imputation (and proportionally to the size of the LLOQ for that specific assay) (Francis et al, 2021). Finally, the additive error for all samples obtained from a specific assay was bound to be at least 20% of the LLOQ of that assay.…”

Pharmacokinetic and pharmacodynamic features of antiretroviral products

“…EFV связывается напрямую с обратной транскриптазой и ингибирует активность вирусной РНК-и ДНК-зависимой ДНК-полимеразы, нарушая каталитический сайт. Хотя комплекс лекарственное средство-ОТ-матрица может продолжать связывать дезоксинуклеозидтрифосфат и катализировать его включение во вновь формирующуюся вирусную ДНК, он делает это медленнее, что и объясняет такую длительную эффективность препарата [31]. Также он имеет длительный терминальный период полувыведения (T 1 ⁄2 =35-50 ч), вследствие чего EFV может сохраняться в низких концентрациях в плазме крови до нескольких недель после прекращения лечения.…”