Impact of CYP2B6 genotype, tuberculosis therapy, and formulation on efavirenz pharmacokinetics in infants and children under 40 months of age.
Journal
AIDS (London, England)
ISSN: 1473-5571
Titre abrégé: AIDS
Pays: England
ID NLM: 8710219
Informations de publication
Date de publication:
15 03 2022
15 03 2022
Historique:
pubmed:
8
12
2021
medline:
9
4
2022
entrez:
7
12
2021
Statut:
ppublish
Résumé
Dosing efavirenz (EFV) in children less than 3 years of age is challenging due to large variability in drug levels. This study evaluated differences in pharmacokinetics with tuberculosis (TB) therapy, formulation, age, and CYP2B6 genotype. Pharmacokinetic data from three IMPAACT/PACTG studies (P382, P1021, and P1070) for children initiating therapy less than 40 months of age were evaluated. Pharmacokinetic data were combined in a population pharmacokinetic model. Exposure from the 2-week pharmacokinetic visit was compared with changes in viral RNA between the Week 0 and Week 4 visits. The model included 103 participants (19 on TB therapy). CYP2B6 516 genotype information was available for 82 participants (TT: 15, GT: 28, GG: 39). Median age at the first pharmacokinetic visit was 17.0 months (range: 2.0-39.0 months). Liquid formulation led to a 42% decrease in bioavailability compared with opened capsules. TB therapy (isoniazid and rifampin) led to a 29% decreased clearance, however Monte Carlo simulations demonstrated the majority of participants on TB therapy receiving standard EFV dosing to be in the target area under the curve range. Clearance was 5.3-fold higher for GG than TT genotype and 3.3-fold higher for GT than TT genotype. Age did not have a significant effect on clearance in the final model. Initial viral RNA decay was lower for patients in the lowest quartile of exposures (area under the curves) than for higher quartiles (P = 0.013). EFV dosing should account for CYP2B6 516 genotype and formulation, but does not require adjustment for concurrent TB therapy.
Identifiants
pubmed: 34873089
doi: 10.1097/QAD.0000000000003141
pii: 00002030-202203150-00005
pmc: PMC8881387
mid: NIHMS1761474
doi:
Substances chimiques
Alkynes
0
Anti-HIV Agents
0
Benzoxazines
0
Cyclopropanes
0
CYP2B6 protein, human
EC 1.14.14.1
Cytochrome P-450 CYP2B6
EC 1.14.14.1
efavirenz
JE6H2O27P8
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
525-532Subventions
Organisme : NICHD NIH HHS
ID : HHSN275201800001C
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI068632
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI068616
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD090259
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI106716
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI069536
Pays : United States
Organisme : NICHD NIH HHS
ID : HHSN275201800001I
Pays : United States
Informations de copyright
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
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