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

Abstract

Objective: In AIDS Clinical Trials Group study A5338, concomitant rifampicin, isoniazid, and efavirenz was associated with more rapid plasma medroxyprogesterone acetate (MPA) clearance compared to historical controls without tuberculosis or HIV therapy. We characterized the pharmacogenetics of this interaction.

Methods: In A5338, women receiving efavirenz-based HIV therapy and rifampicin plus isoniazid for tuberculosis underwent pharmacokinetic evaluations over 12 weeks following a 150-mg intramuscular injection of depot MPA. Data were interpreted with nonlinear mixed-effects modelling. Associations between individual pharmacokinetic parameters and polymorphisms relevant to rifampicin, isoniazid, efavirenz, and MPA were assessed.

Results: Of 62 A5338 participants in four African countries, 44 were evaluable for pharmacokinetic associations, with 17 CYP2B6 normal, 21 intermediate, and 6 poor metabolizers, and 5 NAT2 rapid, 20 intermediate, and 19 slow acetylators. There were no associations between either CYP2B6 or NAT2 genotype and MPA Cmin at week 12, apparent clearance, Cmax, area under the concentration-time curve (AUC) or half-life, or unexplained interindividual variability in clearance, and uptake rate constant or mean transit time of the slow-release fraction (P > 0.05 for each). In exploratory analyses, none of 28 polymorphisms in 14 genes were consistently associated with MPA pharmacokinetic parameters, and none withstood correction for multiple testing.

Conclusions: Study A5338 suggested that more frequent depot MPA dosing may be appropriate for women receiving rifampicin, isoniazid, and efavirenz. The present results suggest that knowledge of CYP2B6 metabolizer or NAT2 acetylator status does not inform individualized DMPA dosing in this setting.

Trial registration: ClinicalTrials.gov NCT02412436.

Conflict of interest statement

Declaration of Interests:

David W. Haas, Paxton Baker, Rosie Mngqibisa, Paxton Baker, Ayotunde Omoz-Oarhe, Susan E. Cohn, Jennifer A. Robinson, Helen McIlleron, Sharlaa Badal-Faesen, Paolo Denti, Susan L. Rosenkranz, Jose Francis, Sajeeda Mawlana, Wadzanai P. Samaneka: None

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Figures

Figure 1.. Relationships between CYP2B6 metabolizer status, NAT2 acetylator status, and selected medroxyprogesterone acetate pharmacokinetic parameters among 44 participants.

Top panel: associations of apparent clearance with CYP2B6 metabolizer status (left) and NAT2 acetylator status (right); Bottom panel: associations of trough concentration with CYP2B6 metabolizer status (left) and NAT2 acetylator status (right). The dashed line indicates the MPA therapeutic cut-off of 0.1 ng/mL. All participants received a single 150 mg intramuscular injection of depot medroxyprogesterone acetate. Error bars indicate median and interquartile range. Jonckheere-Terpstra test P-values are shown. MPA = medroxyprogesterone acetate; Cmin = trough concentration.