Associations between CYP2B6 polymorphisms and pharmacokinetics after a single dose of nevirapine or efavirenz in African americans.
BACKGROUND
Polymorphisms in CYP2B6 affect the steady-state plasma concentrations of nevirapine and efavirenz. In many resource-limited countries, a single dose of nevirapine has been widely prescribed to pregnant women at delivery, to reduce mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1). We characterized associations between genetic polymorphisms and the pharmacokinetics of single doses of nevirapine and efavirenz.


METHODS
Plasma drug concentrations were determined over the 13-day period after administration of a 200-mg oral dose of nevirapine to nonpregnant, HIV-negative African Americans. A 600-mg oral dose of efavirenz was subsequently administered, and pharmacokinetic sampling was repeated. Pharmacokinetic parameters were estimated using a noncompartmental approach. Primary analyses involved 2 CYP2B6 polymorphisms (516G --> T and 983T --> C) known to predict increased steady-state plasma nevirapine and efavirenz exposure. Exploratory analyses involved another 51 polymorphisms in CYP2B6, ABCB1, CYP3A4, and CYP3A5.


RESULTS
On the basis of the composite CYP2B6 516/983 genotype, the 34 participants comprised 10 extensive, 17 intermediate, and 7 slow metabolizer genotypes. The composite CYP2B6 516/983 genotype was significantly associated with plasma drug exposure and clearance for efavirenz but not nevirapine. Exploratory analyses suggested possible associations between additional CYP2B6 polymorphisms and the pharmacokinetics of nevirapine and efavirenz.


CONCLUSIONS
Selective pressure for drug-resistant HIV-1 after administration of single-dose nevirapine may not differ substantially according to CYP2B6 516/983 genotype. Additional polymorphisms, genes, and populations warrant further study.
Haas
David W
DW
USA. david.w.haas@vanderbilt.edu
Gebretsadik
Tebeb
T
Mayo
Gail
G
Menon
Usha N
UN
Acosta
Edward P
EP
Shintani
Ayumi
A
Floyd
Michael
M
Stein
C Michael
CM
Wilkinson
Grant R
GR
D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D044383:Black People / Q000235:genetics*; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D005838:Genotype; D018023:HIV Seronegativity; D006801:Humans; D015810:Linkage Disequilibrium; D008657:Metabolic Clearance Rate; D019829:Nevirapine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D012449:Safety; D001741:Black or African American
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D019829:Nevirapine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz