Dataset Information

Population pharmacogenetic-based pharmacokinetic modeling of efavirenz, 7-hydroxy- and 8-hydroxyefavirenz.

ABSTRACT: The purpose of this study was to determine the demographic and pharmacogenetic covariates that influence the disposition of efavirenz (EFV) and its major metabolites. A population pharmacokinetic (PK) model was developed from a randomized, cross-over, drug-interaction study in healthy male Korean subjects (n?=?17). Plasma concentrations of EFV and its hydroxy-metabolites (0-120?hours) were measured by LC/MS/MS. Genomic DNA was genotyped for variants in the cytochrome P450 (CYP) 2A6, 2B6, 3A5, and MDR1 genes. A PK model was built in a stepwise procedure using nonlinear mixed effect modeling in NONMEM 7. The covariate model was built using the generalized additive modeling and forward selection-backward elimination. Model-based simulations were performed to predict EFV steady-state concentrations following 200, 400, and 600?mg daily oral dose among different CYP2B6 genotypes. The final model included only CYP2B6 genotype as a covariate that predicts EFV clearance through the formation of 8-OH EFV that represented 65% to 80% of EFV clearance. The total clearance of EFV in CYP2B6*6/*6 genotype was ?30% lower than CYP2B6*1/*1 or CYP2B6*1/*6 alleles (P?

SUBMITTER: Abdelhady AM

PROVIDER: S-EPMC4412845 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Population pharmacogenetic-based pharmacokinetic modeling of efavirenz, 7-hydroxy- and 8-hydroxyefavirenz.

Abdelhady A M AM Desta Z Z Jiang F F Yeo C W CW Shin J G JG Overholser B R BR

Journal of clinical pharmacology 20131119 1

The purpose of this study was to determine the demographic and pharmacogenetic covariates that influence the disposition of efavirenz (EFV) and its major metabolites. A population pharmacokinetic (PK) model was developed from a randomized, cross-over, drug-interaction study in healthy male Korean subjects (n = 17). Plasma concentrations of EFV and its hydroxy-metabolites (0-120 hours) were measured by LC/MS/MS. Genomic DNA was genotyped for variants in the cytochrome P450 (CYP) 2A6, 2B6, 3A5, an ...[more]

PMID: 24142869

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Project description:BACKGROUND: Implication of pharmacogenetic variations and efavirenz pharmacokinetics in concomitant efavirenz based antiviral therapy and anti-tubercular drug induced liver injury (DILI) has not been yet studied. We performed a prospective case-control association study to identify the incidence, pharmacogenetic, pharmacokinetic and biochemical predictors for anti-tubercular and antiretroviral drugs induced liver injury (DILI) in HIV and tuberculosis (TB) co-infected patients. METHODS AND FINDINGS: Newly diagnosed treatment naïve TB-HIV co-infected patients (n?=?353) were enrolled to receive efavirenz based ART and rifampicin based anti-TB therapy, and assessed clinically and biochemically for DILI up to 56 weeks. Quantification of plasma efavirenz and 8-hydroxyefaviernz levels and genotyping for NAT2, CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 genes were done. The incidence of DILI and identification of predictors was evaluated using survival analysis and the Cox Proportional Hazards Model. The incidence of DILI was 30.0%, or 14.5 per 1000 person-week, and that of severe was 18.4%, or 7.49 per 1000 person-week. A statistically significant association of DILI with being of the female sex (p?=?0.001), higher plasma efavirenz level (p?=?0.009), efavirenz/8-hydroxyefavirenz ratio (p?=?0.036), baseline AST (p?=?0.022), ALT (p?=?0.014), lower hemoglobin (p?=?0.008), and serum albumin (p?=?0.007), NAT2 slow-acetylator genotype (p?=?0.039) and ABCB1 3435TT genotype (p?=?0.001). CONCLUSION: We report high incidence of anti-tubercular and antiretroviral DILI in Ethiopian patients. Between patient variability in systemic efavirenz exposure and pharmacogenetic variations in NAT2, CYP2B6 and ABCB1 genes determines susceptibility to DILI in TB-HIV co-infected patients. Close monitoring of plasma efavirenz level and liver enzymes during early therapy and/or genotyping practice in HIV clinics is recommended for early identification of patients at risk of DILI.

Project description:BackgroundPharmacogenetics 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.MethodsIn 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.ResultsEFV 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.ConclusionResults 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.

Project description:Compartment modeling is a widely accepted technique in the field of pharmacokinetic analysis. However, conventional compartment modeling is performed under a homogeneity assumption that is not a naturally occurring condition. Since the assumption lacks physiological considerations, the respective modeling approach has been questioned, as novel drugs are increasingly characterized by physiological or physical features. Alternative approaches have focused on fractal kinetics, but evaluations of their application are lacking. Thus, in this study, a simulation was performed to identify desirable fractal-kinetics applications in conventional modeling. Visible changes in the profiles were then investigated. Five cases of finalized population models were collected for implementation. For model diagnosis, the objective function value (OFV), Akaike's information criterion (AIC), and corrected Akaike's information criterion (AICc) were used as performance metrics, and the goodness of fit (GOF), visual predictive check (VPC), and normalized prediction distribution error (NPDE) were used as visual diagnostics. In most cases, model performance was enhanced by the fractal rate, as shown in a simulation study. The necessary parameters of the fractal rate in the model varied and were successfully estimated between 0 and 1. GOF, VPC, and NPDE diagnostics show that models with the fractal rate described the data well and were robust. In the simulation study, the fractal absorption process was, therefore, chosen for testing. In the estimation study, the rate application yielded improved performance and good prediction-observation agreement in early sampling points, and did not cause a large shift in the original estimation results. Thus, the fractal rate yielded explainable parameters by setting only the heterogeneity exponent, which reflects true physiological behavior well. This approach can be expected to provide useful insights in pharmacological decision making.

Dataset Information

Population pharmacogenetic-based pharmacokinetic modeling of efavirenz, 7-hydroxy- and 8-hydroxyefavirenz.

Publications

Population pharmacogenetic-based pharmacokinetic modeling of efavirenz, 7-hydroxy- and 8-hydroxyefavirenz.

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