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 Strom, Gregory P. Bisson, Richard Aplenc, Robert Gross

Research output: Contribution to journalArticle

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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 (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.

Original languageEnglish (US)
Pages (from-to)678-688
Number of pages11
JournalPharmacogenomics Journal
Volume18
Issue number5
DOIs
StatePublished - Sep 1 2018

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efavirenz
Botswana
Cytochrome P-450 Enzyme System
Pharmacokinetics
HIV
Single Nucleotide Polymorphism
Treatment Failure
Isoenzymes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

Vujkovic, Marijana ; Bellamy, Scarlett L. ; Zuppa, Athena F. ; Gastonguay, Marc R. ; Moorthy, Ganesh S. ; Ratshaa, Bakgaki ; Han, Xiaoyan ; Steenhoff, Andrew P. ; Mosepele, Mosepele ; Strom, Brian ; Bisson, Gregory P. ; Aplenc, Richard ; Gross, Robert. / Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana. In: Pharmacogenomics Journal. 2018 ; Vol. 18, No. 5. pp. 678-688.
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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 (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.",
author = "Marijana Vujkovic and Bellamy, {Scarlett L.} and Zuppa, {Athena F.} and Gastonguay, {Marc R.} and Moorthy, {Ganesh S.} and Bakgaki Ratshaa and Xiaoyan Han and Steenhoff, {Andrew P.} and Mosepele Mosepele and Brian Strom and Bisson, {Gregory P.} and Richard Aplenc and Robert Gross",
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Vujkovic, M, Bellamy, SL, Zuppa, AF, Gastonguay, MR, Moorthy, GS, Ratshaa, B, Han, X, Steenhoff, AP, Mosepele, M, Strom, B, Bisson, GP, Aplenc, R & Gross, R 2018, 'Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana', Pharmacogenomics Journal, vol. 18, no. 5, pp. 678-688. https://doi.org/10.1038/s41397-018-0028-2

Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana. / Vujkovic, Marijana; Bellamy, Scarlett L.; Zuppa, Athena F.; Gastonguay, Marc R.; Moorthy, Ganesh S.; Ratshaa, Bakgaki; Han, Xiaoyan; Steenhoff, Andrew P.; Mosepele, Mosepele; Strom, Brian; Bisson, Gregory P.; Aplenc, Richard; Gross, Robert.

In: Pharmacogenomics Journal, Vol. 18, No. 5, 01.09.2018, p. 678-688.

Research output: Contribution to journalArticle

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T1 - Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana

AU - Vujkovic, Marijana

AU - Bellamy, Scarlett L.

AU - Zuppa, Athena F.

AU - Gastonguay, Marc R.

AU - Moorthy, Ganesh S.

AU - Ratshaa, Bakgaki

AU - Han, Xiaoyan

AU - Steenhoff, Andrew P.

AU - Mosepele, Mosepele

AU - Strom, Brian

AU - Bisson, Gregory P.

AU - Aplenc, Richard

AU - Gross, Robert

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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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