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Pharmacogenomics J. 2018 Sep;18(5):678-688. doi: 10.1038/s41397-018-0028-2. Epub 2018 Jun 1.

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

Author information

1
Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
2
Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Drexel University, Philadelphia, PA, USA.
3
Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
4
Metrum Research Group, Tariffville, CT, USA.
5
Botswana UPenn Partnership, Gaborone, Botswana.
6
Division of Infectious Diseases, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
7
Faculty of Medicine, University of Botswana, Gaborone, Botswana.
8
Rutgers Biomedical and Health Sciences, Newark, NJ, USA.
9
Department of Medicine (Infectious Diseases), University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
10
Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
11
Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. grossr@upenn.edu.
12
Department of Medicine (Infectious Diseases), University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. grossr@upenn.edu.

Abstract

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 (pā€‰=ā€‰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.

PMID:
29855606
PMCID:
PMC6151142
DOI:
10.1038/s41397-018-0028-2
[Indexed for MEDLINE]
Free PMC Article

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