TY - JOUR
T1 - Pharmacogenetic interactions of efavirenz or rifampin and isoniazid with levonorgestrel emergency contraception during treatment of HIV or tuberculosis
AU - Agyemang, Nana
AU - Scarsi, Kimberly K.
AU - Baker, Paxton
AU - Smeaton, Laura M.
AU - Podany, Anthony T.
AU - Olefsky, Maxine
AU - Woolley, Elizabeth
AU - Barr, Elizabeth
AU - Pham, Michelle
AU - Mawlana, Sajeeda
AU - Supparatpinyo, Khuanchai
AU - Gatechompol, Sivaporn
AU - Jalil, Emilia M.
AU - Gadama, Luis
AU - Badal-Faesen, Sharlaa
AU - Van Schalkwyk, Marije
AU - Kayama, Cecelia
AU - Belaunzaran-Zamudio, Pablo F.
AU - Godfrey, Catherine
AU - Cohn, Susan E.
AU - Mngqibisa, Rosie
AU - Haas, David W.
N1 - Funding Information:
This work was supported by the National Institute of Allergy and Infectious Diseases [grant number UM1 AI068634, UM1 AI068636 and UM1 AI106701] and the Eunice Kennedy Shriver National Institute of Child Health and Human Development [grant number R01 HD085887 to KS]. Additional support included AI069439, AI110527, AI077505, AI120790, and TR002243 (David Haas). Nana Agyemang was supported by R25 AI164610 (Chandravanu Dash, PI). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders of the study oversaw the development and monitoring of the study but had no role in the conduct, analyses, and conclusions of the study.
Publisher Copyright:
© 2023 Lippincott Williams and Wilkins. All rights reserved.
PY - 2023/8/1
Y1 - 2023/8/1
N2 - Objective In AIDS Clinical Trials Group study A5375, a pharmacokinetic trial of levonorgestrel emergency contraception, double-dose levonorgestrel (3 mg, versus standard dose 1.5 mg) offset the induction effects of efavirenz or rifampin on plasma levonorgestrel exposure over 8 h post-dose (AUC0-8h). We characterized the pharmacogenetics of these interactions. Methods Cisgender women receiving efavirenz- or dolutegravir-based HIV therapy, or on isoniazid-rifampin for tuberculosis, were followed after a single oral dose of levonorgestrel. Linear regression models, adjusted for BMI and age, characterized associations of CYP2B6 and NAT2 genotypes (which affect plasma efavirenz and isoniazid exposure, respectively) with levonorgestrel pharmacokinetic parameters. Results Of 118 evaluable participants, 17 received efavirenz/levonorgestrel 1.5 mg, 35 efavirenz/levonorgestrel 3 mg, 34 isoniazid-rifampin/levonorgestrel 3 mg, and 32 (control group) dolutegravir/levonorgestrel 1.5 mg. There were 73 Black and 33 Asian participants. Regardless of genotype, women on efavirenz and isoniazid-rifampin had higher levonorgestrel clearance. In the efavirenz/levonorgestrel 3 mg group, CYP2B6 normal/intermediate metabolizers had levonorgestrel AUC0-8hvalues similar to controls, while CYP2B6 poor metabolizers had AUC0-8hvalues of 40% lower than controls. In the isoniazid-rifampin group, NAT2 rapid/intermediate acetylators had levonorgestrel AUC0-8hvalues similar to controls, while NAT2 slow acetylators had AUC0-8hvalues 36% higher than controls. Conclusion CYP2B6 poor metabolizer genotypes exacerbate the efavirenz-levonorgestrel interaction, likely by increased CYP3A induction with higher efavirenz exposure, making the interaction more difficult to overcome. NAT2 slow acetylator genotypes attenuate the rifampin-levonorgestrel interaction, likely by increased CYP3A inhibition with higher isoniazid exposure.
AB - Objective In AIDS Clinical Trials Group study A5375, a pharmacokinetic trial of levonorgestrel emergency contraception, double-dose levonorgestrel (3 mg, versus standard dose 1.5 mg) offset the induction effects of efavirenz or rifampin on plasma levonorgestrel exposure over 8 h post-dose (AUC0-8h). We characterized the pharmacogenetics of these interactions. Methods Cisgender women receiving efavirenz- or dolutegravir-based HIV therapy, or on isoniazid-rifampin for tuberculosis, were followed after a single oral dose of levonorgestrel. Linear regression models, adjusted for BMI and age, characterized associations of CYP2B6 and NAT2 genotypes (which affect plasma efavirenz and isoniazid exposure, respectively) with levonorgestrel pharmacokinetic parameters. Results Of 118 evaluable participants, 17 received efavirenz/levonorgestrel 1.5 mg, 35 efavirenz/levonorgestrel 3 mg, 34 isoniazid-rifampin/levonorgestrel 3 mg, and 32 (control group) dolutegravir/levonorgestrel 1.5 mg. There were 73 Black and 33 Asian participants. Regardless of genotype, women on efavirenz and isoniazid-rifampin had higher levonorgestrel clearance. In the efavirenz/levonorgestrel 3 mg group, CYP2B6 normal/intermediate metabolizers had levonorgestrel AUC0-8hvalues similar to controls, while CYP2B6 poor metabolizers had AUC0-8hvalues of 40% lower than controls. In the isoniazid-rifampin group, NAT2 rapid/intermediate acetylators had levonorgestrel AUC0-8hvalues similar to controls, while NAT2 slow acetylators had AUC0-8hvalues 36% higher than controls. Conclusion CYP2B6 poor metabolizer genotypes exacerbate the efavirenz-levonorgestrel interaction, likely by increased CYP3A induction with higher efavirenz exposure, making the interaction more difficult to overcome. NAT2 slow acetylator genotypes attenuate the rifampin-levonorgestrel interaction, likely by increased CYP3A inhibition with higher isoniazid exposure.
KW - CYP2B6
KW - HIV therapy
KW - NAT2
KW - efavirenz
KW - emergency contraception
KW - isoniazid
KW - levonorgestrel
KW - pharmacogenetics
KW - rifampin
KW - tuberculosis
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U2 - 10.1097/FPC.0000000000000501
DO - 10.1097/FPC.0000000000000501
M3 - Article
C2 - 37306344
AN - SCOPUS:85164292990
SN - 1744-6872
VL - 33
SP - 126
EP - 135
JO - Pharmacogenetics and genomics
JF - Pharmacogenetics and genomics
IS - 6
ER -
