David W Haas1,2, Rosie Mngqibisa3, Jose Francis4, Helen McIlleron4, Jennifer A Robinson5, Michelle A Kendall6, Paxton Baker7, Sajeeda Mawlana3, Sharlaa Badal-Faesen8, Francis Angira9, Ayotunde Omoz-Oarhe10, Wadzanai P Samaneka11, Paolo Denti4, Susan E Cohn12. 1. Department of Medicine, Vanderbilt University School of Medicine. 2. Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee, USA. 3. Enhancing Care Foundation, Durban International CRS, Wentworth Hospital, Durban. 4. Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. 5. Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland. 6. Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. 7. Vanderbilt Technologies for Advanced Genomics, Vanderbilt University Medical Center, Nashville, TN, USA. 8. Clinical HIV Research Unit, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. 9. Kenya Medical Research Institute, Center for Global Health Research (KEMRI/CGHR)/Emory-CDC CTU, Kisumu, Kenya. 10. Botswana Clinical Trials Unit, Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana. 11. Parirenyatwa CRS, University of Zimbabwe Clinical Trials Research Centre, Harare, Zimbabwe. 12. Northwestern University Feinberg School of Medicine, Infectious Diseases Division, Chicago, Illinois, USA.
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.
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.
Authors: Zeruesenay Desta; Roseann S Gammal; Li Gong; Michelle Whirl-Carrillo; Aditya H Gaur; Chonlaphat Sukasem; Jennifer Hockings; Alan Myers; Marelize Swart; Rachel F Tyndale; Collen Masimirembwa; Otito F Iwuchukwu; Sanika Chirwa; Jeffrey Lennox; Andrea Gaedigk; Teri E Klein; David W Haas Journal: Clin Pharmacol Ther Date: 2019-07-05 Impact factor: 6.875
Authors: Kimberly K Scarsi; Yoninah S Cramer; Susan L Rosenkranz; Francesca Aweeka; Baiba Berzins; Robert W Coombs; Kristine Coughlin; Laura E Moran; Carmen D Zorrilla; Victor Akelo; Mariam Aziz; Ruth K Friedman; David Gingrich; Shobha Swaminathan; Catherine Godfrey; Susan E Cohn Journal: Lancet HIV Date: 2019-09 Impact factor: 12.767
Authors: D Heather Watts; Jeong-Gun Park; Susan E Cohn; Song Yu; Jane Hitti; Alice Stek; Pamela A Clax; Laila Muderspach; Juan J L Lertora Journal: Contraception Date: 2007-12-21 Impact factor: 3.375