Influence of host genetic factors on efavirenz plasma and intracellular pharmacokinetics in HIV-1-infected patients

• Published in: Pharmacogenomics Vol. 11; no. 9; pp. 1223 - 1234
• Main Authors: Elens, Laure, Vandercam, Bernard, Yombi, Jean-Cyr, Lison, Dominique, Wallemacq, Pierre, Haufroid, Vincent
• Format: Journal Article
• Language: English
• Published: England Future Medicine Ltd 01.09.2010
• Subjects: ABCB1; Adult; Alleles; antiretroviral drug; Aryl Hydrocarbon Hydroxylases - genetics; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Benzoxazines - blood; Benzoxazines - pharmacokinetics; CD4 antigen; CYP2A6; CYP2B6; CYP3A5; Cytochrome P-450 CYP2A6; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP3A - genetics; Dosage and administration; Drug therapy; Efavirenz; Female; Gene Frequency; Gene polymorphism; Genetic factors; Genotype; Glucuronosyltransferase - genetics; HIV; HIV infection; HIV Infections - blood; HIV Infections - drug therapy; HIV Infections - genetics; HIV-1 - genetics; Human immunodeficiency virus; Humans; Identification and classification; Leukocytes, Mononuclear - metabolism; Male; Oxidoreductases, N-Demethylating - genetics; Peripheral blood mononuclear cells; Pharmacogenetics; Pharmacokinetics; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Regression Analysis; Reverse Transcriptase Inhibitors - blood; Reverse Transcriptase Inhibitors - pharmacokinetics; Single nucleotide polymorphisms; Single-nucleotide polymorphism; SNP; UGT2B7; Belgium
• ISSN: 1462-2416; 1744-8042; 1744-8042
• DOI: 10.2217/pgs.10.94

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. 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. EFV concentrations in plasma ([EFV] ) and in peripheral blood mononuclear cells ([EFV] ) were determined in 50 HIV-infected patients. Subjects were genotyped for 13 polymorphisms in 5 different genes ( , , , and ). Relationships between genetic status and [EFV] , [EFV] or EFV accumulation in peripheral blood mononuclear cells (EFV accumulation ratio or accumulation ration [AR]) were then evaluated. allelic status was associated with differences in [EFV] but also in [EFV] . Patients carrying at least one mutated allele showed significantly higher [EFV] and [EFV] than homozygous wild-type (mutated homozygous [m/m] >heterozygous [wt/m]>homozygous wild-type [wt/wt], p<0.001). rs3842T>C was significantly associated with higher EFV AR (p = 0.032). Finally, the 3435C>T SNP was associated with a lower increase in CD4-cell count after EFV therapy initiation. Our study corroborates previous findings indicating that knowledge of genetic status should be taken into account for an EFV treatment. Our results also constitute the first demonstration of the significant influence of genetic polymorphisms on [EFV] and suggest that SNPs may also influence the clinical impact of EFV treatment.