TY - JOUR
T1 - Pharmacokinetics and Drug-Drug Interactions of Isoniazid and Efavirenz in Pregnant Women Living With HIV in High TB Incidence Settings
T2 - Importance of Genotyping
AU - IMPAACT P1078 (TB APPRISE) Study Group Team
AU - Gausi, Kamunkhwala
AU - Wiesner, Lubbe
AU - Norman, Jennifer
AU - Wallis, Carole L.
AU - Onyango-Makumbi, Carolyne
AU - Chipato, Tsungai
AU - Haas, David W.
AU - Browning, Renee
AU - Chakhtoura, Nahida
AU - Montepiedra, Grace
AU - Aaron, Lisa
AU - McCarthy, Katie
AU - Bradford, Sarah
AU - Vhembo, Tichaona
AU - Stranix-Chibanda, Lynda
AU - Masheto, Gaerolwe R.
AU - Violari, Avy
AU - Mmbaga, Blandina T.
AU - Aurpibul, Linda
AU - Bhosale, Ramesh
AU - Nevrekhar, Neetal
AU - Rouzier, Vanessa
AU - Kabugho, Enid
AU - Mutambanengwe, Mercy
AU - Chanaiwa, Vongai
AU - Nyati, Mandisa
AU - Mhembere, Tsungai
AU - Tongprasert, Fuanglada
AU - Hesseling, Anneke
AU - Shin, Katherine
AU - Zimmer, Bonnie
AU - Costello, Diane
AU - Jean-Philippe, Patrick
AU - Sterling, Timothy R.
AU - Theron, Gerhard
AU - Weinberg, Adriana
AU - Gupta, Amita
AU - Denti, Paolo
N1 - Publisher Copyright:
© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
PY - 2021/4
Y1 - 2021/4
N2 - The World Health Organization guidelines recommend that individuals living with HIV receive ≥ 6 months of isoniazid preventive therapy, including pregnant women. Yet, plasma isoniazid exposure during pregnancy, in the antiretroviral therapy era, has not been well-described. We investigated pregnancy-induced and pharmacogenetic-associated pharmacokinetic changes and drug-drug interactions between isoniazid and efavirenz in pregnant women. Eight hundred forty-seven women received isoniazid for 28 weeks, either during pregnancy or at 12 weeks postpartum, and 786 women received efavirenz. After adjusting for NAT2 and CYP2B6 genotype and weight, pregnancy increased isoniazid and efavirenz clearance by 26% and 15%, respectively. Isoniazid decreased efavirenz clearance by 7% in CYP2B6 normal metabolizers and 13% in slow and intermediate metabolizers. Overall, both isoniazid and efavirenz exposures were reduced during pregnancy, but the main determinants of drug concentration were NAT2 and CYP2B6 genotypes, which resulted in a five-fold difference for both drugs between rapid and slow metabolizers.
AB - The World Health Organization guidelines recommend that individuals living with HIV receive ≥ 6 months of isoniazid preventive therapy, including pregnant women. Yet, plasma isoniazid exposure during pregnancy, in the antiretroviral therapy era, has not been well-described. We investigated pregnancy-induced and pharmacogenetic-associated pharmacokinetic changes and drug-drug interactions between isoniazid and efavirenz in pregnant women. Eight hundred forty-seven women received isoniazid for 28 weeks, either during pregnancy or at 12 weeks postpartum, and 786 women received efavirenz. After adjusting for NAT2 and CYP2B6 genotype and weight, pregnancy increased isoniazid and efavirenz clearance by 26% and 15%, respectively. Isoniazid decreased efavirenz clearance by 7% in CYP2B6 normal metabolizers and 13% in slow and intermediate metabolizers. Overall, both isoniazid and efavirenz exposures were reduced during pregnancy, but the main determinants of drug concentration were NAT2 and CYP2B6 genotypes, which resulted in a five-fold difference for both drugs between rapid and slow metabolizers.
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U2 - 10.1002/cpt.2044
DO - 10.1002/cpt.2044
M3 - Article
C2 - 32909316
AN - SCOPUS:85092569887
SN - 0009-9236
VL - 109
SP - 1034
EP - 1044
JO - Clinical pharmacology and therapeutics
JF - Clinical pharmacology and therapeutics
IS - 4
ER -