12 research outputs found
Pharmacogenetic-based efavirenz dose modification: suggestions for an African population and the different CYP2B6 genotypes.
Pharmacogenetics contributes to inter-individual variability in pharmacokinetics (PK) of efavirenz (EFV), leading to variations in both efficacy and toxicity. The purpose of this study was to assess the effect of genetic factors on EFV pharmacokinetics, treatment outcomes and genotype based EFV dose recommendations for adult HIV-1 infected Ugandans.In total, 556 steady-state plasma EFV concentrations from 99 HIV infected patients (64 female) treated with EFV/lamivudine/zidovidine were analyzed. Patient genotypes for CYP2B6 (*6 & *11), CYP3A5 (*3,*6 & *7) and ABCB1 c.4046A>G, baseline biochemistries and CD4 and viral load change from baseline were determined. A one-compartment population PK model with first-order absorption (NONMEM) was used to estimate genotype effects on EFV pharmacokinetics. PK simulations were performed based upon population genotype frequencies. Predicted AUCs were compared between the product label and simulations for doses of 300 mg, 450 mg, and 600 mg.EFV apparent clearance (CL/F) was 2.2 and 1.74 fold higher in CYP2B6*6 (*1/*1) and CYP2B6*6 (*1/*6) compared CYP2B6*6 (*6/*6) carriers, while a 22% increase in F1 was observed for carriers of ABCB1 c.4046A>G variant allele. Higher mean AUC was attained in CYP2B6 *6/*6 genotypes compared to CYP2B6 *1/*1 (p<0.0001). Simulation based AUCs for 600 mg doses were 1.25 and 2.10 times the product label mean AUC for the Ugandan population in general and CYP2B6*6/*6 genotypes respectively. Simulated exposures for EFV daily doses of 300 mg and 450 mg are comparable to the product label. Viral load fell precipitously on treatment, with only six patients having HIV RNA >40 copies/mL after 84 days of treatment. No trend with exposure was noted for these six patients.Results of this study suggest that daily doses of 450 mg and 300 mg might meet the EFV treatment needs of HIV-1 infected Ugandans in general and individuals homozygous for CYP2B6*6 mutation, respectively
Baseline characteristics and <i>CYP2B6*6</i> and <i>ABCB1</i> (<i>c.4046A>G)</i> genotypes of the study participants (n = 99).
<p>Missing was assigned to individuals whose genotypes were not determined. Data presented in the table are the assignments as analyzed.</p
Area under the curve (AUC) NONMEM estimate values for ABCB1 c. 4046A>G and or CYP2B6* 6 genotypes.
<p>The estimations are based on the predicted individual apparent clearance and bioavailability values.</p><p>mut = heterozygous plus homozygous variant, wt = homozygous variants.</p><p>Four patients did not have a reported ABCB1 genotype and one patient was ABCB1 G/G. These five subjects are not included in these summary statistics for ABCB1, but are included in the general CYP2B6*6 summary above.</p
HIV viral loads at baseline and day 84 of treatment and AUC of study participants who failed to attain viral suppression to below detection by day 84.
<p>Data are arranged in order of increasing AUC.</p
The individually weighted residuals (WRES) are plotted <i>vs.</i> time.
<p>The dashed line is the zero reference line while the solid line is a smooth nonparametric regression line. The plot demonstrates a good fit of all time point concentration data by the model.</p
Summary of significant factors in the covariate analysis; forward inclusion (α = 0.05) followed by backward elimination (α = 0.01).
Final model pharmacokinetic parameters.
<p>Ka = Mean population absorption rate constant, V = Mean population Volume of distribution, CL = Mean population clearance, F1 = Bioavailability fraction, IIV CL = inter-individual variability on Clearance in the population, RV = residual variability.</p
Distribution of estimated patient AUC values by CYP2B6 genotype.
<p>CYP2B6*1/*1, CYP2B6 *1/*6, and CYP2B6 *6/*6. Dotted line = the mean AUC value in the product label.</p
Simulation based AUC for 300
a<p>The frequency of each group in these simulations reflects the proportional frequency of the groups in the observed patient dataset.</p
Goodness of Fit.
<p>Individual predicted EFV concentrations (IPRED) versus observed concentrations, by CYP2B6*6 genotype (B66).</p