Predictive value of known and novel alleles of CYP2B6 for efavirenz plasma concentrations in HIV-infected individuals.
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.
Rotger
M
M
Institute of Microbiology, University of Lausanne, Lausanne, Switzerland.
Tegude
H
H
Colombo
S
S
Cavassini
M
M
Furrer
H
H
Décosterd
L
L
Blievernicht
J
J
Saussele
T
T
Günthard
H F
HF
Schwab
M
M
Eichelbaum
M
M
Telenti
A
A
Zanger
U M
UM
D000328:Adult; D000480:Alkynes; D000483:Alleles; D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D048588:Benzoxazines; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000097:blood* / Q000235:genetics*; D006801:Humans; D008297:Male; D010078:Oxazines / Q000097:blood*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D010957:Plasmids / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011446:Prospective Studies; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz