The aims of this ANRS12154 open-label, single-center, multiple-dose
pharmacokinetic study were to characterize nevirapine pharmacokinetics
in a Cambodian population of HIV-infected patients and to identify
environmental and genetic factors of variability, focusing on
the
CYP2B6,
CYP3A5, and
ABCB1 (
MDR1) genes. A total of 170 Cambodian
HIV-infected patients were included. Nevirapine trough concentrations
were measured after 18 and 36 months of starting antiretroviral
treatment and in samples drawn during a dosing interval in a
subset of 10 patients. All data were analyzed by nonlinear mixed-effects
modeling. The effect of covariates was investigated using the
population pharmacokinetic model. Patients carrying homozygous
loss-of-function alleles
CYP3A5 6986A>
G,
CYP2B6 516G>
T,
CYP2B6 1459C>
T, and
ABCB1 3435C>
T represent 42.4%, 9.2%,
0%, and 18% of the population, respectively. The median nevirapine
trough concentrations did not differ after 18 and 36 months
of treatment (5,705 ng/ml [range,
50 to 13,871] and 5,709 ng/ml
[range,
50 to 15,422], respectively). Interpatient and intrapatient
variabilities of nevirapine apparent clearance were 28% and
17%, respectively.
CYP2B6 516G>
T and creatinine clearance
were found to significantly affect nevirapine apparent clearance.
The estimated nevirapine apparent clearances were 2.95 liters/h,
2.62 liters/h, and 1.86 liters/h for
CYP2B6 516GG,
CYP2B6 516GT,
and
CYP2B6 516TT genotypes, respectively. The impact of creatinine
clearance was small. This study demonstrates that 95% of the
patients had sustained nevirapine exposure well above the 3,000-ng/ml
threshold. Nevirapine clearance was shown to be affected by
CYP2B6 516G>
T genetic polymorphism and creatinine clearance,
although this explained only part of the interpatient variability,
which remains low compared to that for other antiretroviral
drugs.
Antimicrobial Agents and Chemotherapy, October 2010, p. 4432-4439, Vol. 54, No. 10
0066-4804/10/$12.00+0 doi:10.1128/AAC.00512-10
No comments:
Post a Comment