Influence of CYP2B6 516G&gt;T polymorphism and interoccasion variability (IOV) on the population pharmacokinetics of efavirenz in HIV-infected South African children

Viljoen, Michelle; Karlsson, Mats O.; Meyers, Tammy; Gous, Hermien; Dandara, Collet; Rheeders, Malie

doi:10.1007/s00228-011-1148-7

Cited by 24 publications

(52 citation statements)

References 48 publications

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“…Data from Africa have repeatedly replicated the association between efavirenz exposure and both CYP2B6 516G→T and CYP2B6 983T→C , but data from Africa beyond these two polymorphisms are limited. We characterized relationships between genetic polymorphisms and plasma efavirenz concentrations among HIV‐infected adults and children in South Africa.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetics of plasma efavirenz exposure in HIV‐infected adults and children in South Africa

Sinxadi

Leger

McIlleron

et al. 2015

Brit J Clinical Pharma

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AIMS Genetic factors, notably CYP2B6 516G→T [rs3745274] and 983T→C[rs28399499], explain much of the interindividual variability in efavirenz pharmacokinetics, but data from Africa are limited. We characterized relationships between genetic polymorphisms and plasma efavirenz concentrations in HIV-infected Black South African adults and children. METHODSSteady-state mid-dosing interval efavirenz concentrations were measured. We genotyped 241 polymorphisms in genes potentially relevant to efavirenz metabolism and transport, including ABCB1, CYP2A6, CYP2B6, CYP3A4, CYP3A5, NR1I2 and NR1I3. ). Among individual CYP2B6 polymorphisms, 516G→T best predicted efavirenz concentrations (β = 0.22, 95% CI 0.13, 0.30, P = 1.27 × 10 RESULTS Among À6). There was also associations with 983T→C (β = 0.27, 95% CI 0.10, 0.44, P = 0.002) and 15582C→T (β = 0.11, 95% CI 0.01, 0.22, P = 0.04). Associations were consistent in adults and children. No other polymorphisms were independently associated with efavirenz concentrations. CONCLUSIONSComposite CYP2B6 genotype based on CYP2B6 516G→T, 983T→C, and 15582C→T best described efavirenz exposure in HIV-infected Black South African adults and children. WHAT IS ALREADY KNOWN ABOUT THE SUBJECT• The polymorphisms CYP2B6 516G→T (rs3745274) and 983T→C (rs28399499) are strongly associated with plasma efavirenz concentrations, but do not entirely explain interindividual variability.• A recent genome-wide association study implicated CYP2B6 15582C→T (rs4803419) as an independent predictor of efavirenz trough concentrations.• Reported pharmacokinetic associations beyond CYP2B6 are inconsistent. WHAT THIS STUDY ADDS• We provide evidence to show that CYP2B6 15582C→T is associated with plasma efavirenz concentrations in Black South Africans, in addition to CYP2B6 516G→T and 983T→C.• We show that genetic associations are consistent in adults and children.• We found no additional associations with plasma efavirenz concentrations beyond these CYP2B6 polymorphisms.

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Section: Introductionmentioning

confidence: 99%

Pharmacogenetics of plasma efavirenz exposure in HIV‐infected adults and children in South Africa

Sinxadi

Leger

McIlleron

et al. 2015

Brit J Clinical Pharma

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“…4 Although the high variability in efavirenz PK in children has been thoroughly studied, 12–15 analyses successfully relating observed drug exposures to treatment response and detecting other determinants of treatment failure are limited. 9,10,16 Factors affecting efavirenz effectiveness have often been investigated independently of drug concentrations with inconclusive findings across studies 8,9,17–20 ; similarly, the effect of high efavirenz exposure on increased risk of CNS adverse events (AEs) is unconfirmed in children.…”

Section: Introductionmentioning

confidence: 99%

Plasma Efavirenz Exposure, Sex, and Age Predict Virological Response in HIV-Infected African Children

Bienczak

Denti

Cook

et al. 2016

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…Sources of EFV pharmacokinetics (PK) variability have been studied in adults (7)(8)(9)(10)(11) and in children (12)(13)(14)(15)(16). These data have shown the influence of weight and genetics on the pharmacokinetics of EFV.…”

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confidence: 99%

Pharmacokinetics of Efavirenz at a High Dose of 25 Milligrams per Kilogram per Day in Children 2 to 3 Years Old

Pressiat

Amorissani‐Folquet

Yonaba

et al. 2017

Antimicrob Agents Chemother

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The MONOD ANRS 12206 trial was designated to assess simplification of a successful lopinavir (LPV)-based antiretroviral treatment in HIV-infected children younger than 3 years of age using efavirenz (EFV; 25 mg/kg of body weight/day) to preserve the class of protease inhibitors for children in that age group. In this substudy, EFV concentrations were measured to check the consistency of an EFV dose of 25 mg/kg and to compare it with the 2016 FDA recommended dose. Fifty-two children underwent blood sampling for pharmacokinetic study at 6 months and 12 months after switching to EFV. We applied a Bayesian approach to derive EFV pharmacokinetic parameters using the nonlinear mixed-effect modeling (NONMEM) program. The proportion of midinterval concentrations 12 h after drug intake (C 12 h ) corresponding to the EFV therapeutic pharmacokinetic thresholds (1 to 4 mg/liter) was assessed according to different dose regimens (25 mg/kg in the MONOD study versus the 2016 FDA recommended dose). With both the 25 mg/kg/day dose and the 2016 FDA recommended EFV dose, simulations showed that the majority of C 12 h values were within the therapeutic range (62.6% versus 62.8%). However, there were more children underexposed with the 2016 FDA recommended dose (11.6% versus 1.2%). Conversely, there were more concentrations above the threshold of toxicity with the 25 mg/kg dose (36.2% versus 25.6%), with C 12 h values of up to 15 mg/liter. Only 1 of 52 children was switched back to LPV because of persistent sleeping disorders, but his C 12 h value was within therapeutic ranges. A high EFV dose of 25 mg/kg per day in children under 3 years old achieved satisfactory therapeutic effective levels. However, the 2016 FDA recommended EFV dose appeared to provide more acceptable safe therapeutic profiles. (This study has been registered at ClinicalTrials.gov under identifier NCT01127204.)

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Influence of CYP2B6 516G>T polymorphism and interoccasion variability (IOV) on the population pharmacokinetics of efavirenz in HIV-infected South African children

Cited by 24 publications

References 48 publications

Pharmacogenetics of plasma efavirenz exposure in HIV‐infected adults and children in South Africa

Pharmacogenetics of plasma efavirenz exposure in HIV‐infected adults and children in South Africa

Plasma Efavirenz Exposure, Sex, and Age Predict Virological Response in HIV-Infected African Children

Pharmacokinetics of Efavirenz at a High Dose of 25 Milligrams per Kilogram per Day in Children 2 to 3 Years Old

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