TY - JOUR
T1 - CYP2B6 (c.516G→T) and CYP2A6 (*9B and/or *17) polymorphisms are independent predictors of efavirenz plasma concentrations in HIV-infected patients
AU - Kwara, Awewura
AU - Lartey, Margaret
AU - Sagoe, Kwamena W.
AU - Rzek, Naser L.
AU - Court, Michael H.
PY - 2009/4
Y1 - 2009/4
N2 - AIMS Interindividual variability in efavirenz pharmacokinetics is not entirely explained by the well-recognized CYP2B6 516G→T single nucleotide polymorphism. The aim of this study was to determine whether polymorphisms in the CYP2A6 gene can be used to enhance the predictability of efavirenz concentrations in human immunodeficiency virus (HIV)-infected native African patients. METHODS Mid-dose efavirenz plasma concentrations were determined at 4 and 8 weeks following initiation of antiretroviral therapy in 65 HIV-infected Ghanaian patients. Selected CYP2B6 and CYP2A6 genotypes were determined by commercial 5′-nuclease assays. Relationships between averaged 4- and 8-week mid-dose efavirenz concentrations, demographic variables and genotypes were evaluated by univariate and multivariate statistical approaches including gene-gene interactions. RESULTS CYP2B6 c.516G→T, CYP2B6 c.983T→C, CYP2A6*9B and CYP2A6*17 allele frequencies were 45, 4, 5 and 12%, respectively. Rifampicin therapy, gender, age and body mass index had no significant influence on efavirenz mid-dose concentrations. Median efavirenz concentrations were more than five times higher (P < 0.001) in patients with CYP2B6 c.516TT genotype compared with GG and GT genotypes. Although none of the CYP2A6 genotypes was associated with altered efavirenz concentrations individually, CYP2A6*9B and/or CYP2A6*17 carriers showed a 1.8 times higher median efavirenz concentration (P = 0.017) compared with noncarriers. Multiple linear regression analysis indicated that the CYP2B6 c.516G→T polymorphism and CYP2A6 slow-metabolizing variants accounted for as much as 36 and 12% of the total variance in efavirenz concentrations, respectively. CONCLUSIONS Our findings support previous work showing efavirenz oxidation by CYP2A6, and suggest that both CYP2A6 and CYP2B6 genotyping may be useful for predicting efavirenz plasma concentrations.
AB - AIMS Interindividual variability in efavirenz pharmacokinetics is not entirely explained by the well-recognized CYP2B6 516G→T single nucleotide polymorphism. The aim of this study was to determine whether polymorphisms in the CYP2A6 gene can be used to enhance the predictability of efavirenz concentrations in human immunodeficiency virus (HIV)-infected native African patients. METHODS Mid-dose efavirenz plasma concentrations were determined at 4 and 8 weeks following initiation of antiretroviral therapy in 65 HIV-infected Ghanaian patients. Selected CYP2B6 and CYP2A6 genotypes were determined by commercial 5′-nuclease assays. Relationships between averaged 4- and 8-week mid-dose efavirenz concentrations, demographic variables and genotypes were evaluated by univariate and multivariate statistical approaches including gene-gene interactions. RESULTS CYP2B6 c.516G→T, CYP2B6 c.983T→C, CYP2A6*9B and CYP2A6*17 allele frequencies were 45, 4, 5 and 12%, respectively. Rifampicin therapy, gender, age and body mass index had no significant influence on efavirenz mid-dose concentrations. Median efavirenz concentrations were more than five times higher (P < 0.001) in patients with CYP2B6 c.516TT genotype compared with GG and GT genotypes. Although none of the CYP2A6 genotypes was associated with altered efavirenz concentrations individually, CYP2A6*9B and/or CYP2A6*17 carriers showed a 1.8 times higher median efavirenz concentration (P = 0.017) compared with noncarriers. Multiple linear regression analysis indicated that the CYP2B6 c.516G→T polymorphism and CYP2A6 slow-metabolizing variants accounted for as much as 36 and 12% of the total variance in efavirenz concentrations, respectively. CONCLUSIONS Our findings support previous work showing efavirenz oxidation by CYP2A6, and suggest that both CYP2A6 and CYP2B6 genotyping may be useful for predicting efavirenz plasma concentrations.
KW - CYP2A6
KW - CYP2B6
KW - Efavirenz concentration
KW - Rifampicin
UR - http://www.scopus.com/inward/record.url?scp=63849281439&partnerID=8YFLogxK
U2 - 10.1111/j.1365-2125.2009.03368.x
DO - 10.1111/j.1365-2125.2009.03368.x
M3 - Article
C2 - 19371316
AN - SCOPUS:63849281439
SN - 0306-5251
VL - 67
SP - 427
EP - 436
JO - British Journal of Clinical Pharmacology
JF - British Journal of Clinical Pharmacology
IS - 4
ER -