Population Pharmacokinetic/Pharmacogenetic Model for Optimization of Efavirenz Therapy in Caucasian HIV-Infected Patients

Sánchez, A. M. Martín; Cabrera, Salvador; Santos, Dolores; Valverde, María P.; Fuertes, Antonio B.; Domínguez-Gil, A; García, Maria José

doi:10.1128/aac.00194-11

Cited by 42 publications

(42 citation statements)

References 54 publications

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“…Accordingly, BSV in CL/F was increased from 25.7% to 35.2% when CYP2B6 metabolizer status was removed from the final model (37% increase in variability). Our results are similar to those of other studies that demonstrate a significant effect of CYP2B6 genotypes on CL/F and a 25 to 50% reduction in unexplained BSV upon accounting for CYP2B6*6 or CYP2B6 c.516G-to-T alleles (2,26,27,34). It is expected that the CYP2B6 variants evaluated in this study account for the majority of the influence of CYP2B6 genetic variability on efavirenz concentrations in the population studied, given the relatively low allelic frequency and/or minor effects of additional variants (28,35).…”

Section: Discussionsupporting

confidence: 82%

Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

Robarge

Metzger

et al. 2017

Antimicrob Agents Chemother

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Efavirenz pharmacokinetics is characterized by large between-subject variability, which determines both therapeutic response and adverse effects. Some of the variability in efavirenz pharmacokinetics has been attributed to genetic variability in cytochrome P450 genes that alter efavirenz metabolism, such as CYP2B6 and CYP2A6. While the effects of additional patient factors have been studied, such as sex, weight, and body mass index, the extent to which they contribute to variability in efavirenz exposure is inconsistently reported. The aim of this analysis was to develop a pharmacometric model to quantify the contribution of genetic and nongenetic factors to efavirenz pharmacokinetics. A population-based pharmacokinetic model was developed using 1,132 plasma efavirenz concentrations obtained from 73 HIV-seronegative volunteers administered a single oral dose of 600 mg efavirenz. A two-compartment structural model with absorption occurring by zero-and firstorder processes described the data. Allometric scaling adequately described the relationship between fat-free mass and apparent oral clearance, as well as fat mass and apparent peripheral volume of distribution. Inclusion of fat-free mass and fat mass in the model mechanistically accounted for correlation between these disposition parameters and sex, weight, and body mass index. Apparent oral clearance of efavirenz was reduced by 25% and 51% in subjects predicted to have intermediate and slow CYP2B6 metabolizer status, respectively. The final pharmacokinetic model accounting for fat-free mass, fat mass, and CYP2B6 metabolizer status was consistent with known mechanisms of efavirenz disposition, efavirenz physiochemical properties, and pharmacokinetic theory. (This study has been registered at ClinicalTrials.gov under identifier NCT00668395.) KEYWORDS body composition, cytochrome P450 2B6 (CYP2B6), efavirenz, population pharmacokinetics E favirenz is a nonnucleoside reverse transcriptase inhibitor that is used in combination with nucleoside/nucleotide reverse transcriptase inhibitors to treat HIVinfected individuals older than 3 years who are naive to antiretroviral drugs. Due to its proven efficacy and low cost relative to newer antiretrovirals, efavirenz-based therapy remains the preferred first-line regimen in many low-income nations and is consequently one of the most commonly prescribed antiretroviral drugs (1). Efavirenz pharmacokinetics (PK) is characterized by large interindividual variability in plasma concentrations following a single dose (2, 3) and during chronic administration (4), which has important clinical implications. During the induction phase, efavirenz exposure is associated with central nervous system and psychiatric adverse events, liver enzyme elevation, and rash, among others (5, 6). This may result in increasing rates of

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Section: Discussionsupporting

confidence: 82%

Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

Robarge

Metzger

et al. 2017

Antimicrob Agents Chemother

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“…Table 1 shows the results from the simulation and a number of clinical studies and popPK studies. The mean/median observed plasma concentrations of EFV ranged from 1,973 ng ml Ϫ1 to 3,180 ng ml Ϫ1 (9,(15)(16)(17)(18). Simulated CL, V SS , and K a values were 1.04-fold, 1.28-fold, and 0.6-fold different, respectively, from observed data (18).…”

Section: Resultsmentioning

confidence: 90%

Efavirenz Is Predicted To Accumulate in Brain Tissue: an In Silico , In Vitro , and In Vivo Investigation

Curley

Rajoli

Moss

et al. 2017

Antimicrob Agents Chemother

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Adequate concentrations of efavirenz in the central nervous system (CNS) are necessary to suppress viral replication, but high concentrations may increase the likelihood of CNS adverse drug reactions. The aim of this investigation was to evaluate the efavirenz distribution in the cerebrospinal fluid (CSF) and the brain by using a physiologically based pharmacokinetic (PBPK) simulation for comparison with rodent and human data. The efavirenz CNS distribution was calculated using a permeability-limited model on a virtual cohort of 100 patients receiving efavirenz (600 mg once daily). Simulation data were then compared with human data from the literature and with rodent data. Wistar rats were administered efavirenz (10 mg kg of body weight Ϫ1 ) once daily over 5 weeks. Plasma and brain tissue were collected for analysis via liquid chromatography-tandem mass spectrometry (LC-MS/ MS). The median maximum concentrations of drug (C max ) were predicted to be 3,184 ng ml Ϫ1 (interquartile range [IQR], 2,219 to 4,851 ng ml Ϫ1 ), 49.9 ng ml Ϫ1 (IQR, 36.6 to 69.7 ng ml Ϫ1 ), and 50,343 ng ml Ϫ1 (IQR, 38,351 to 65,799 ng ml Ϫ1 ) in plasma, CSF, and brain tissue, respectively, giving a tissue-to-plasma ratio of 15.8. Following 5 weeks of oral dosing of efavirenz (10 mg kg Ϫ1 ), the median plasma and brain tissue concentrations in rats were 69.7 ng ml Ϫ1 (IQR, 44.9 to 130.6 ng ml Ϫ1 ) and 702.9 ng ml Ϫ1 (IQR, 475.5 to 1,018.0 ng ml Ϫ1 ), respectively, and the median tissue-to-plasma ratio was 9.5 (IQR, 7.0 to 10.9). Although it is useful, measurement of CSF concentrations may give an underestimation of the penetration of antiretrovirals into the brain. The limitations associated with obtaining tissue biopsy specimens and paired plasma and CSF samples from patients make PBPK modeling an attractive tool for probing drug distribution.

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“…This requires the random assignment of pharmacokinetic parameters whose distributions are obtained from the reported pharmacokinetic models (see Supplementary Material for a brief description of these models). For the considered treatments, pharmacokinetic drug parameters were taken from reported studies 25, 26, 27, 28. For therapy combining efavirenz, emtricitabine, and tenofovir DF, we did not consider medication interactions in absorption or elimination; efavirenz is mostly eliminated by the liver, while the other two medications are eliminated by the kidneys without noticeable interaction 29…”

Section: Methodsmentioning

confidence: 99%

A Mathematical Model to Predict HIV Virological Failure and Elucidate the Role of Lymph Node Drug Penetration

Sanche

Sheehan

Mésplède

et al. 2017

CPT Pharmacom & Syst Pharma

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Preventing virological failure following HIV treatment remains a difficult task that is further complicated by the emergence of drug resistance. We have developed a mathematical model able to explain and predict HIV virological outcomes for various compounds and patients' drug intake patterns. Compared to current approaches, this model considers, altogether, drug penetration into lymph nodes, a refined adherence representation accounting for the propensity for long drug holidays, population pharmacokinetic and pharmacodynamic variability, drug interaction, and crossresistance. In silico results are consistent with clinical observations for treatment with efavirenz, efavirenz in association with tenofovir DF and emtricitabine, or boosted darunavir. Our findings indicate that limited lymph node drug penetration can account for a large proportion of cases of virological failure and drug resistance. Since a limited amount of information is required by the model, it can be of use in the process of drug discovery and to guide clinical treatment strategies.

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Population Pharmacokinetic/Pharmacogenetic Model for Optimization of Efavirenz Therapy in Caucasian HIV-Infected Patients

Cited by 42 publications

References 54 publications

Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

Efavirenz Is Predicted To Accumulate in Brain Tissue: an In Silico , In Vitro , and In Vivo Investigation

A Mathematical Model to Predict HIV Virological Failure and Elucidate the Role of Lymph Node Drug Penetration

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