CYP2B6*6, CYP2B6*18, Body weight and sex are predictors of efavirenz pharmacokinetics and treatment response: population pharmacokinetic modeling in an HIV/AIDS and TB cohort in Zimbabwe

Dhoro, Milcah; Zvada, Simbarashe; Ngara, Bernard; Nhachi, Charles; Kadzirange, Gerald; Chonzi, Prosper; Masimirembwa, Collen

doi:10.1186/s40360-015-0004-2

Cited by 66 publications

(59 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…BMI has been reported to be positively correlated with efavirenz V p /F, inversely correlated with AUC, and uncorrelated with terminal elimination half-life (3). However, other studies have also concluded there is no impact of weight or BMI on V p /F (27, 44) or did not report whether these effects were considered (15,25,40). Weight-normalized apparent volume of distribution has been reported to be 1.6-fold larger in females than males, suggesting that a sex-dependent factor influenced V/F independent of weight (16).…”

Section: Discussionmentioning

confidence: 91%

“…Therefore, we retained the allometric FFM scalar and suggest that TBW-and FFM-scaled efavirenz clearance be further evaluated over a broader weight range that is biased toward obese subjects. Reported sex differences in efavirenz CL/F have been conflicting, with some studies showing associations (3,40) and others reporting no relationship (15,16). Similarly, differences in CYP2B6 expression and activity in human liver microsomes between sexes have been inconsistent in the literature (41-43).…”

Section: Discussionmentioning

confidence: 91%

See 1 more Smart Citation

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

Robarge

Metzger

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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

show abstract

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 91%

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

Robarge

Metzger

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…With the EFV full-profile model developed, the sparse plasma concentrations were fit together with full-profile plasma data. As strong prior literature suggests that differences in CYP2B6*6 genotypes are linked to variability in exposure measures of EFV (22,34,(36)(37)(38), CYP2B6*6 genotype status was included as a modifier of clearance in the base model. Individuals with CYP2B6*1/*1, CYP2B6*1/*6, and CYP2B6*6/*6 genotypes were modeled with unique (thetas) for EFV clearance.…”

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

Habtewold

Aklillu

Makonnen

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The objectives of this study were to characterize the population pharmacokinetics (PK) of efavirenz (EFV) and 8-hydroxy-efavirenz (8OHEFV) in plasma and peripheral blood mononuclear cells (PBMCs) and to explore covariates affecting the PK parameters. Fifty-one patients had steady-state 0-to-24-h concentrations of EFV and 8OHEFV in plasma with corresponding concentrations in PBMCs, while 261 patients had one or two sparse concentrations at 16 Ϯ 1 h postdose at weeks 4 and/or 16. The pharmacogenetic markers CYP2B6*6, CYP3A5*3, CYP3A5*6, UGT2B7*2, ABCB1 (3435C¡T, 3842A¡G), OATP1B1*1B, and OATP1B1*5, the presence of a rifampin-based antituberculosis (anti-TB) regimen, baseline body weight and organ function values, and demographic factors were explored as covariates. EFV concentration data were well described by a two-compartment model with first-order absorption (K a ) and absorption lag time (A lag ) (K a ϭ 0.2 h Ϫ1 ; A lag ϭ 0.83 h; central compartment clearance [CL c /F] for CYP2B6*1/*1 ϭ 18 liters/h, for CYP2B6*1/*6 ϭ 14 liters/h, and for CYP2B6*6/*6 ϭ 8.6 liters/h) and PBMCs as a peripheral compartment. EFV transfer from plasma to PBMCs was first order (CL p /F ϭ 32 liters/h), followed by capacity-limited return (V max ϭ 4,400 ng/ml/h; K m ϭ 710 ng/ml). Similarly, 8OHEFV displayed a first-order elimination and distribution to PBMCs, with a capacity-limited return to plasma. No covariate relationships resulted in a significant explanation of interindividual variability (IIV) on the estimated PK parameters of EFV and 8OHEFV, except for CYP2B6*6 genotypes, which were consistent with prior evidence. Both EFV and 8OHEFV accumulated to higher concentrations in PBMCs than in plasma and were well described by first-order input and Michaelis-Menten kinetics removal from PBMCs. CYP2B6*6 genotype polymorphisms were associated with decreased EFV and 8OHEFV clearance.KEYWORDS efavirenz, 8-hydroxy-efavirenz, peripheral blood mononuclear cells, population pharmacokinetics E favirenz (EFV)-based antiretroviral therapy remains the preferred first-line treatment option in important international guidelines, including those of the World Health Organization (1). EFV displays a wide between-patient pharmacokinetic (PK) variability (2, 3). This is ascribed partially to genetic variation of the CYP2B6 enzyme, which is primarily responsible for the metabolism of efavirenz to 8-hydroxy-efavirenz (8OHEFV) (4, 5). Efavirenz is described to have a narrow safety margin (6-8). In addition, a couple

show abstract

“…Being one of the potent drugs preventing mother to child transmission of HIV, EFV drug has been investigated for pharmacokinetic variability, therapeutic effects, and toxicity among different patient populations. [14][15][16] It has been observed that a very strict pharmacological concentration is a must in order to avoid virologic failure and tissue toxicity. Therefore, it was worth investigating the nanoformulation of EFV for anti-HIV activity and toxicity in GALT.…”

Section: Introductionmentioning

confidence: 99%

Preparation and characterization of anti-HIV nanodrug targeted to microfold cell of gut-associated lymphoid tissue

Roy

Ding

Pilakka-Kanthikeel

et al. 2015

IJN

View full text Add to dashboard Cite

The human immunodeficiency virus 1 (HIV-1) still remains one of the leading life-threatening diseases in the world. The introduction of highly active antiretroviral therapy has significantly reduced disease morbidity and mortality. However, most of the drugs have variable penetrance into viral reservoir sites, including gut-associated lymphoid tissue (GALT). Being the largest lymphoid organ, GALT plays a key role in early HIV infection and host–pathogen interaction. Many different treatment options have been proposed to eradicate the virus from GALT. However, it becomes difficult to deliver traditional drugs to the GALT because of its complex physiology. In this regard, we developed a polymer-based Pluronic nanocarrier containing anti-HIV drug called efavirenz (EFV) targeting Microfold cells (M-cells) in the GALT. M-cells are specialized epithelial cells that are predominantly present in the GALT. In this work, we have exploited this paracellular transport property of M-cells for targeted delivery of Pluronic nanocarrier tagged EFV, bioconjugated with anti-M-cell-specific antibodies to the GALT (nanodrug). Preliminary characterization showed that the nanodrug (EFV-F12-COOH) is of 140 nm size with 0.3 polydispersion index, and the zeta potential of the particles was −19.38±2.2 mV. Further, drug dissolution study has shown a significantly improved sustained release over free drugs. Binding potential of nanodrug with M-cell was also confirmed with fluorescence microscopy and in vitro uptake and release studies. The anti-HIV activity of the nanodrug was also significantly higher compared to that of free drug. This novel formulation was able to show sustained release of EFV and inhibit the HIV-1 infection in the GALT compared to the free drug. The present study has potential for our in vivo targeted nanodrug delivery system by combining traditional enteric-coated capsule technique via oral administration.

show abstract

CYP2B66, CYP2B618, Body weight and sex are predictors of efavirenz pharmacokinetics and treatment response: population pharmacokinetic modeling in an HIV/AIDS and TB cohort in Zimbabwe

Cited by 66 publications

References 42 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

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

Preparation and characterization of anti-HIV nanodrug targeted to microfold cell of gut-associated lymphoid tissue

Contact Info

Product

Resources

About