Influence of host genetic factors on efavirenz plasma and intracellular pharmacokinetics in HIV-1-infected patients.
BACKGROUND
Efavirenz (EFV) is characterized by interindividual pharmacokinetic variability causing inconsistent clinical responses. Previous studies have identified some possible genetic determinants of the variability in plasma concentrations. However, their impact on EFV intracellular pharmacokinetics remains mostly unexplored.


OBJECTIVE
To confirm previous observations concerning the influence of genetic polymorphisms on EFV plasma concentrations and to assess their effect on the intracellular pharmacokinetics of EFV.


METHODS
EFV concentrations in plasma ([EFV](Cmin)) and in peripheral blood mononuclear cells ([EFV](CC)) were determined in 50 HIV-infected patients. Subjects were genotyped for 13 polymorphisms in 5 different genes (CYP2A6, CYP2B6, CYP3A5, UGT2B7 and ABCB1). Relationships between genetic status and [EFV](Cmin), [EFV](CC) or EFV accumulation in peripheral blood mononuclear cells (EFV accumulation ratio or accumulation ration [AR]) were then evaluated.


RESULTS
CYP2B6 allelic status was associated with differences in [EFV](Cmin) but also in [EFV](CC). Patients carrying at least one mutated allele showed significantly higher [EFV](Cmin) and [EFV](CC) than homozygous wild-type (mutated homozygous [m/m] >heterozygous [wt/m]>homozygous wild-type [wt/wt], p<0.001). ABCB1 rs3842T>C was significantly associated with higher EFV AR (p = 0.032). Finally, the ABCB1 3435C>T SNP was associated with a lower increase in CD4-cell count after EFV therapy initiation.


CONCLUSIONS
Our study corroborates previous findings indicating that knowledge of CYP2B6 genetic status should be taken into account for an EFV treatment. Our results also constitute the first demonstration of the significant influence of CYP2B6 genetic polymorphisms on [EFV](CC) and suggest that ABCB1 SNPs may also influence the clinical impact of EFV treatment.
Elens
Laure
L
Louvain Centre for Toxicology & Applied Pharmacology, Université Catholique de Louvain, 53.02, Avenue E. Mounier, 1200 Bruxelles, Belgium. laure.elens@uclouvain.be
Vandercam
Bernard
B
Yombi
Jean-Cyr
JC
Lison
Dominique
D
Wallemacq
Pierre
P
Haufroid
Vincent
V
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000480:Alkynes; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D048588:Benzoxazines / Q000097:blood / Q000493:pharmacokinetics*; D003521:Cyclopropanes; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585599:CYP2B6 protein, human; C510164:CYP3A5 protein, human; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; C098320:efavirenz