Predictive value of known and novel alleles of CYP2B6 for efavirenz plasma concentrations in HIV-infected individuals

Rotger, M; Tegude, H; Colombo, S; Cavassini, M; Furrer, H; Décosterd, L; Blievernicht, J; Saussele, T; Günthard, H F; Schwab, M; Eichelbaum, M; Telenti, A; Zanger, U M (2007). Predictive value of known and novel alleles of CYP2B6 for efavirenz plasma concentrations in HIV-infected individuals. Clinical pharmacology & therapeutics, 81(4), pp. 557-66. New York, N.Y.: Nature Publishing Group 10.1038/sj.clpt.6100072

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To assess the association of CYP2B6 allelic diversity with efavirenz (EFV) pharmacokinetics, we performed extensive genotyping of 15 relevant single nucleotide polymorphism in 169 study participants, and full resequencing of CYP2B6 in individuals with abnormal EFV plasma levels. Seventy-seven (45.5%) individuals carried a known (CYP2B6*6, *11, *15, or *18) or new loss/diminished-function alleles. Resequencing defined two new loss-of-function alleles: allele *27 (marked by 593T>C [M198T]), that results in 85% decrease in enzyme activity and allele *28 (marked by 1132C>T), that results in protein truncation at arginine 378. Median AUC levels were 188.5 microg h/ml for individuals homozygous for a loss/diminished-function allele, 58.6 microg h/ml for carriers, and 43.7 microg h/ml for noncarriers (P<0.0001). Individuals with a poor metabolizer genotype had a likelihood ratio of 35 (95% CI, 11-110) of presenting very high EFV plasma levels. CYP2B6 poor metabolizer genotypes explain to a large extent EFV pharmacokinetics and identify individuals at risk of extremely elevated EFV plasma levels.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Infectiology

UniBE Contributor:

Furrer, Hansjakob

ISSN:

0009-9236

ISBN:

17235330

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:59

Last Modified:

04 May 2014 23:17

Publisher DOI:

10.1038/sj.clpt.6100072

PubMed ID:

17235330

Web of Science ID:

000245435900014

URI:

https://boris.unibe.ch/id/eprint/25684 (FactScience: 60466)

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