TY - JOUR
T1 - Pharmacokinetics and pharmacodynamics of depot medroxyprogesterone acetate in african women receiving treatment for human immunodeficiency virus and tuberculosis
T2 - Potential concern for standard dosing frequency
AU - Mngqibisa, Rosie
AU - Kendall, Michelle A.
AU - Dooley, Kelly
AU - Wu, Xingye
AU - Firnhaber, Cynthia
AU - McIlleron, Helen
AU - Robinson, Jennifer
AU - Cramer, Yoninah
AU - Rosenkranz, Susan L.
AU - Roa, Jhoanna
AU - Coughlin, Kristine
AU - Mawlana, Sajeeda
AU - Badal-Faesen, Sharlaa
AU - Schnabel, David
AU - Omoz-Oarhe, Ayotunde
AU - Samaneka, Wadzanai
AU - Godfrey, Catherine
AU - Cohn, Susan E.
N1 - Funding Information:
The research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under award numbers UM1 AI068634 (Statistical and Data Management Center of the AIDS Clinical Trials Group), UM1 AI068636, UM1 AI69471 and UM1 AI106701. This work was supported in part by the Emory-Centers for Disease Control and Prevention (CDC) HIV/AIDS Clinical Trials Unit award number UM1AI069418 from the NIH (NIAID) and the US CDC (Division of HIV/ AIDS Prevention). Acknowledgments. The authors acknowledge and thank all the participants in ACTG A5338 and all ACTG personnel who made this study possible. The authors gratefully acknowledge the support of the ACTG network and the scientific committees for their contribution during protocol development and study conduct. The authors especially want to acknowledge and thank Susan L. Rosenkranz, Yoninah Cramer, and Kristine Coughlin for their contributions in study design, data monitoring, and interim analysis. The authors also wish to acknowledge the following study team members for their contributions: Gary Maartens, Zephne Van Der Spuy, David Haas, Akbar Shahkolahi, Jhoanna C. Roa, Laura Moran, Michelle Wildman, Ian S. Mugisa, Asuman Ssentamu, Vandana Kulkarni, and Flavia Nakayima Miiro. A sincere thank you to Jennifer Norman and her team at the University of Cape Town Speciality Laboratory for the analysis of MPA and progesterone samples. The authors acknowledge the following sites, site staff, and investigators for performing all the work at their various sites: Sr P. Madlala and M. Chikowore, Durban International Clinical Research Site 11201, UM1 AI069432-08; Drs M. Rassool and T. Mwelase, University of the Witwatersrand Helen Joseph CRS 11101 UM1 AI069463 (Clinical Trials Unit grant number) and AI068636 (ACTG network grant number); and Drs F. A. Mbata, E. Ouma Kisumu, and K. Cain, Kisumu CRS 31460, 5UM1AI068636. Dr U. Chakalisa and M. S. Raesi Gaborone CRS 12701, UM1 AI069456-08; and Prof J. G. Hakim and Dr P. Mukwekwerere, Parirenyatwa CRS 30313 UM1AI069436.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - Background. Effective contraception is critical to young women with HIV-associated tuberculosis (TB), as unintended pregnancy is associated with increased perinatal morbidity and mortality. The effects of co-administration of efavirenz and rifampicin on the pharmacokinetics of depot medroxyprogesterone acetate (DMPA) are unknown. We hypothesized that clearance of medroxyprogesterone acetate (MPA) would increase when given with rifampicin and efavirenz, thus increasing risk of ovulation. Methods. This pharmacokinetics (PK) study assessed DMPA among HIV/TB coinfected women on an efavirenz-based antiretroviral treatment and rifampicin-based TB treatment. Plasma MPA concentrations and progesterone were measured predose (MPA only) and 2, 4, 6, 8, 10, and 12 weeks after a single DMPA 150 mg intramuscular injection. The primary outcome measure, MPA concentration (<0.1 ng/mL) at week 12, was assessed using exact 95% Clopper-Pearson confidence intervals. MPA PK parameters were calculated using noncompartmental analysis. Results. Among 42 PK-evaluable women from 5 African countries, median age was 32 years and median CD4 was 414 cells/ mm3. Five women (11.9%; 95% CI, 4.0-25.6%) had MPA <0.1 ng/mL at week 12; of these, one had MPA <0.1 ng/mL at week 10. The median clearance of MPA was 19 681 L/week compared with 12 118 L/week for historical controls. There were no adverse events related to DMPA, and progesterone concentrations were <1 ng/mL for all women for the study duration. Conclusions. DMPA, when given with rifampicin and efavirenz, was safe. MPA clearance was higher than in women with HIV not on ART, leading to subtherapeutic concentrations of MPA in 12% of women, suggesting that more frequent dosing might be needed.
AB - Background. Effective contraception is critical to young women with HIV-associated tuberculosis (TB), as unintended pregnancy is associated with increased perinatal morbidity and mortality. The effects of co-administration of efavirenz and rifampicin on the pharmacokinetics of depot medroxyprogesterone acetate (DMPA) are unknown. We hypothesized that clearance of medroxyprogesterone acetate (MPA) would increase when given with rifampicin and efavirenz, thus increasing risk of ovulation. Methods. This pharmacokinetics (PK) study assessed DMPA among HIV/TB coinfected women on an efavirenz-based antiretroviral treatment and rifampicin-based TB treatment. Plasma MPA concentrations and progesterone were measured predose (MPA only) and 2, 4, 6, 8, 10, and 12 weeks after a single DMPA 150 mg intramuscular injection. The primary outcome measure, MPA concentration (<0.1 ng/mL) at week 12, was assessed using exact 95% Clopper-Pearson confidence intervals. MPA PK parameters were calculated using noncompartmental analysis. Results. Among 42 PK-evaluable women from 5 African countries, median age was 32 years and median CD4 was 414 cells/ mm3. Five women (11.9%; 95% CI, 4.0-25.6%) had MPA <0.1 ng/mL at week 12; of these, one had MPA <0.1 ng/mL at week 10. The median clearance of MPA was 19 681 L/week compared with 12 118 L/week for historical controls. There were no adverse events related to DMPA, and progesterone concentrations were <1 ng/mL for all women for the study duration. Conclusions. DMPA, when given with rifampicin and efavirenz, was safe. MPA clearance was higher than in women with HIV not on ART, leading to subtherapeutic concentrations of MPA in 12% of women, suggesting that more frequent dosing might be needed.
KW - DMPA
KW - Efavirenz
KW - HIV
KW - Rifampicin
KW - Tuberculosis
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U2 - 10.1093/cid/ciz863
DO - 10.1093/cid/ciz863
M3 - Article
C2 - 31504342
AN - SCOPUS:85087504953
VL - 71
SP - 517
EP - 524
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
SN - 1058-4838
IS - 3
ER -