The Relationships of ABCB1 3435C&gt;T and CYP2B6 516G&gt;T With High-Density Lipoprotein Cholesterol in HIV-Infected Patients Receiving Efavirenz

Mahungu, TW; Nair, Devaki; Smith, Colette; Egan, Deirdre; Youle, M; Ma, Jun; Khoo, SH; Back, DJ; Owen, Andrew

doi:10.1038/clpt.2009.78

Cited by 14 publications

(11 citation statements)

References 49 publications

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“…Consistent with previous studies in HIV-infected children 3,4,18 and adults 13,19,20 starting efavirenz-or nevirapine-based therapy, HDL concentrations increased over the first years of efavirenz treatment. In our study, an indirect response model assuming that HDL and LDL elimination was inhibited by efavirenz best described the relationship between efavirenz plasma concentration and evolution of HDL and LDL concentrations over time in HIV-infected children.…”

Section: Discussionsupporting

confidence: 89%

A Population Pharmacokinetic/Pharmacodynamic Model Predicts Favorable HDL Cholesterol Changes Over the First 5 Years in Children Treated With Current Efavirenz‐Based Regimens

Homkham

Cressey

Ingsrisawang

et al. 2016

The Journal of Clinical Pharma

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Efavirenz use is associated with changes in cholesterol concentrations, but it is unclear whether this effect is related to drug concentrations. Using efavirenz and cholesterol plasma concentrations measured in 87 antiretroviral-naive children in Thailand, we assessed indirect response models to describe the evolution of high- and low-density lipoprotein (HDL, LDL) cholesterol concentrations in relation to efavirenz plasma concentrations over time where efavirenz was assumed to either stimulate cholesterol production or inhibit its elimination. Simulations of cholesterol evolution for children with different average efavirenz concentrations (Cav ) according to their assumed status of "fast" or "slow" metabolizers of efavirenz were performed. At treatment initiation, children's median (interquartile range, IQR) age was 8 years (5 to 10), body mass index z-score 0.01 (-1.05 to 1.44), HDL 31 mg/dL (24 to 44), and LDL 83 mg/dL (69 to 100). Median (IQR) efavirenz Cav was 1.7 mg/L (1.3 to 2.1) during the period of observation. The best model describing the evolution of HDL and LDL cholesterol concentrations over time assumed that efavirenz inhibited their elimination. HDL concentrations increase over 5 years, whereas LDL concentrations increased only during the first 4 months and then returned to baseline levels afterward. Simulations predicted that, after 3 years, HDL would increase to 63 mg/dL in "fast" metabolizers and 97 mg/dL in "slow" metabolizers of efavirenz. The population pharmacokinetic-pharmacodynamic (PK-PD) model shows that favorable HDL cholesterol changes can be expected in children with current efavirenz dosing guidelines over 5 years of treatment.

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Section: Discussionsupporting

confidence: 89%

A Population Pharmacokinetic/Pharmacodynamic Model Predicts Favorable HDL Cholesterol Changes Over the First 5 Years in Children Treated With Current Efavirenz‐Based Regimens

Homkham

Cressey

Ingsrisawang

et al. 2016

The Journal of Clinical Pharma

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“…Evidence indicates a link of ABCB1 variants with circulating lipid profiles, mainly LDL-C, and the efficacy of statins [26]. Furthermore, ABCB1 3435C>T (rs1045642) has been associated with efavirenz induced changes in HDL-C [32]. We did not observe association with HDL-C response to atenolol at this SNP in our study; however, because we did observe association in this gene, ABCB1 and drug associated HDL-C change warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Atenolol Induced HDL-C Change in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study

et al. 2013

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We sought to identify novel pharmacogenomic markers for HDL-C response to atenolol in participants with mild to moderate hypertension. We genotyped 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study on the Illumina HumanCVD Beadchip. During PEAR, participants were randomized to receive atenolol or hydrochlorothiazide. Blood pressure and cholesterol levels were evaluated at baseline and after treatment. This study focused on participants treated with atenolol monotherapy. Association with atenolol induced HDL-C change was evaluated in 232 whites and 152 African Americans using linear regression. No SNPs achieved a Bonferroni corrected P-value. However, we identified 13 regions with consistent association across whites and African Americans. The most interesting of these regions were seven with prior associations with HDL-C, other metabolic traits, or functional implications in the lipid pathway: GALNT2, FTO, ABCB1, LRP5, STARD3NL, ESR1, and LIPC. Examples are rs2144300 in GALNT2 in whites (P=2.29x10-4, β=-1.85 mg/dL) and rs12595985 in FTO in African Americans (P=2.90x10-4, β=4.52 mg/dL), both with consistent regional association (P<0.05) in the other race group. Additionally, baseline GALNT2 expression differed by rs2144300 genotype in whites (P=0.0279). In conclusion, we identified multiple gene regions associated with atenolol induced HDL-C change that were consistent across race groups, several with functional implications or prior associations with HDL-C.

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“…Genetic variation in the ABCB1 gene influences efavirenz pharmacokinetics 7 and cellular cholesterol transport. 8 Plasma efavirenz concentration displays a wide between-patient variability partly due to ethnic and pharmacogenetic factors. 9 Therefore, interindividual variation in efavirenz exposure due to pharmacogenetic variations may influence the extent of enzyme induction.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic and pharmacokinetic aspects of CYP3A induction by efavirenz in HIV patients

et al. 2012

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We investigated the effects of pharmacogenetic variations and efavirenz pharmacokinetics on inter-individual differences in the extent of CYP3A induction by efavirenz using 4β-hydroxycholesterol/cholesterol (4β-OHC/Chol) as a marker for CYP3A induction. Plasma 4β-hydroxycholesterol and cholesterol concentrations were determined at baseline, and at the 4th, 16th and 48th week of efavirenz-based highly active antiretroviral therapy in antiretroviral therapy-naive HIV patients (n=77). Efavirenz plasma concentrations were quantified at weeks 4 and 16. CYP2B6, CYP3A5, ABCB1, UGT2B7 genotyping were done. Compared with baseline, the median plasma 4β-OHC/Chol ratio increased at the 4th (257%), 16th (291%) and 48th (165%) week (P<0.0001). CYP2B6*6 genotype significantly influenced 4β-OHC/Chol ratio at weeks 16 (P=0.02) and 48 (P=0.04) being highest in CYP2B6*6/*6>*1/*6>*1/*1. There were positive correlations between plasma efavirenz and 4β-OHC/Chol ratios (week 4: P=0.02, week 16: P=0.001). CYP3A enzyme induction by efavirenz is pronounced in CYP2B6 slow metabolizers who have high efavirenz plasma exposure.

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The Relationships of ABCB1 3435C>T and CYP2B6 516G>T With High-Density Lipoprotein Cholesterol in HIV-Infected Patients Receiving Efavirenz

Cited by 14 publications

References 49 publications

A Population Pharmacokinetic/Pharmacodynamic Model Predicts Favorable HDL Cholesterol Changes Over the First 5 Years in Children Treated With Current Efavirenz‐Based Regimens

A Population Pharmacokinetic/Pharmacodynamic Model Predicts Favorable HDL Cholesterol Changes Over the First 5 Years in Children Treated With Current Efavirenz‐Based Regimens

Atenolol Induced HDL-C Change in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study

Pharmacogenetic and pharmacokinetic aspects of CYP3A induction by efavirenz in HIV patients

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