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A Common CYP2B6 Variant Is Associated with Sustiva Pharmacokinetics and Central Nervous System (CNS) Side Effects (20 02 2004)

publié le 23 February 2004

A Common CYP2B6 Variant Is Associated with Sustiva Pharmacokinetics and Central Nervous System (CNS) Side Effects

Sustiva (efavirenz/ EFV) is metabolized by CYP2B6, a polymorphic hepatic mixed function oxidase. Functional differences in CYP2B6 activity have been identified in vitro, but their clinical relevance is uncertain.

These include a G-to-T change at position 516 (G516T) that identifies CYP2B6 *6 and *7 haplotypes. CNS side effects are common with EFV. NWCS 214 examined relationships between EFV CNS toxicity, EFV pharmacokinetics, and genetic polymorphisms.

Antiretroviral-naïve subjects who had received EFV plus nucleoside analogues in Adult AIDS Clinical Trials Group (ACTG) Protocols A5095/A5097s were studied. Blood for population pharmacokinetics analysis was collected at weeks 1, 4, 12, and 24 to provide empirical Bayes estimated pharmacokinetics parameters. CNS side effects were assessed by standardized questionnaires.

Specimens from the ACTG DNA Repository were collected under Protocol A5128. Single nucleotide polymorphisms  in CYP2B6, 3A4, 3A5, and MDR1 were identified by real-time PCR. Genotype comparisons were carried out with non-parametric trend tests. Exploratory multivariate analysis was done with recursive partitioning.

Results

Study subjects included 89 (57%) whites, 50 (32%) blacks, and 15 (10%) Hispanics. Homozygous T/T genotype at position G516T was more common in blacks (20%) than whites (3%) and was associated with lower clearance and higher plasma EFV levels in all subjects, and in white and black subpopulations analyzed separately (p = 0.001 for AUC24h, clearance, C24h, and Cmax for all comparisons).

Median EFV AUC24h according to G/G, G/T, and T/T genotype was 44 (n = 78), 60 (n = 60), and 130 (n = 14) mg*h/L, respectively. The CYP3A4 1B (A392G) G/- genotypes were also associated with higher EFV levels (p <0.001) although A/A genotype was rare among non-whites.

Recursive partitioning also indicated an association between the CYP2B6 G516T genotype and each pharmacokinetic parameter. The CYP3A A392G genotype was also associated with AUC24h. Only the CYP2B (G516T) T/T genotype was associated with  adverse CNS symptoms (p = 0.04).

None of the genotypes studied showed significant associations with initial or short-term virologic or immunologic response to treatment.

Conclusions 

A CYP2B6 allelic variant that may occur more commonly in blacks than whites is associated with approximately 3-fold higher plasma EFV levels between homozygote genotypes during HIV treatment initiation. Interindividual differences in metabolism may in part explain susceptibility to EFV CNS side effects.

02/20/04

Reference D Haas and others. A Common CYP2B6 Variant Is Associated with Efavirenz Pharmacokinetics and Central Nervous System Side Effects: AACTG Study NWCS214. Abstract 133 (oral). Program and Abstracts of the 11th Conference on Retroviruses and Opportunistic Infections (11th CROI). February 8-11, 2004. San Francisco, CA.

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