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Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana
Journal article   Open access   Peer reviewed

Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana

Marijana Vujkovic, Scarlett L Bellamy, Athena F Zuppa, Marc R Gastonguay, Ganesh S Moorthy, Bakgaki Ratshaa, Xiaoyan Han, Andrew P Steenhoff, Mosepele Mosepele, Brian L Strom, …
The pharmacogenomics journal, v 18(5), pp 678-688
Sep 2018
DOI: https://doi.org/10.1038/s41397-018-0028-2
PMID: 29855606
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-117200View
SubmittedOpen Access (License Unspecified),  Open

Abstract

Adult Alleles Benzoxazines - adverse effects Benzoxazines - pharmacokinetics Botswana Central Nervous System - drug effects Cohort Studies Cytochrome P-450 Enzyme System - genetics Female Genotype HIV Infections - drug therapy HIV Infections - genetics Humans Male Polymorphism, Single Nucleotide - genetics Reverse Transcriptase Inhibitors - adverse effects Reverse Transcriptase Inhibitors - pharmacokinetics
Inter-individual variability in efavirenz (EFV) pharmacokinetics and dynamics is dominantly driven by the polymorphism in cytochrome P450 (CYP) isoenzyme 2B6 516G>T. We hypothesized that additional CYP polymorphisms mediate the relationship between CYP2B6 516G>T, EFV metabolism, and clinical events. We investigated 21 SNPs in 814 HIV-infected adults initiating EFV-based therapy in Botswana for population pharmacokinetics, CNS toxicities, and treatment outcomes. Two SNPs (rs28399499 and rs28399433) showed reduced apparent oral EFV clearance. Four SNPs (rs2279345, rs4803417, rs4802101, and rs61663607) showed extensive clearance. Composite CYP2B-mediated EFV metabolism was significantly associated with CNS toxicity (p = 0.04), with extensive metabolizers reporting more and slow and very slow metabolizers reporting less toxicity after 1 month compared to intermediate metabolizers. Composite CYP2B6 metabolism was not associated with composite early treatment failure. In conclusion, our data suggest that CNS-related toxicities might not be solely the result of super-therapeutic parent EFV concentrations in HIV-infected individuals in patients of African ancestry.

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Industry collaboration
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Web of Science research areas
Genetics & Heredity
Pharmacology & Pharmacy
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