Pharmacology considerations for antiretroviral therapy in human immunodeficiency virus (HIV)-infected children

Hoody, Dorie W; Fletcher, Courtney V.

doi:10.1053/j.spid.2003.09.004

Cited by 23 publications

(18 citation statements)

References 33 publications

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“…This is consistent with an increase in hepatic activity (including the metabolism of EFV by CYP2B6) between the ages of 1 and 4 years, exceeding adult levels (9).…”

Section: Discussionsupporting

confidence: 62%

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Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?

Hirt

Urien

Mathieu

et al. 2009

Antimicrob Agents Chemother

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We aimed in this study to describe efavirenz concentration-time courses in treatment-naïve children after once-daily administration to study the effects of age and body weight on efavirenz pharmacokinetics and to test relationships between doses, plasma concentrations, and efficacy. For this purpose, efavirenz concentrations in 48 children were measured after 2 weeks of didanosine-lamivudine-efavirenz treatment, and samples were available for 9/48 children between months 2 and 5 of treatment. Efavirenz concentrations in 200 plasma specimens were measured using a validated high-performance liquid chromatography method. A population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. The estimated minimal and maximal concentrations of efavirenz in plasma (C min and C max , respectively) and the area under the concentration-time curve (AUC) were correlated to the decrease in human immunodeficiency virus type 1 RNA levels after 3 months of treatment. The threshold C min (and AUC) that improved efficacy was determined. The target minimal concentration of 4 mg/liter was considered for toxicity. An optimized dosing schedule that would place the highest percentage of children in the interval of effective and nontoxic concentrations was simulated. The pharmacokinetics of efavirenz was best described by a one-compartment model with first-order absorption and elimination. The mean apparent clearance and volume of distribution for efavirenz were 0.211 liter/h/kg and 4.48 liters/kg, respectively. Clearance decreased significantly with age. When the recommended doses were given to 46 of the 48 children, 19% (44% of children weighing less than 15 kg) had C min s below 1 mg/liter. A significantly higher percentage of children with C min s of >1.1 mg/liter or AUCs of >51 mg/liter ⅐ h than of children with lower values had viral load decreases greater than 2 log 10 copies/ml after 3 months of treatment. Therefore, to optimize the percentage of children with C min s between 1.1 and 4 mg/liter, children should receive the following once-daily efavirenz doses: 25 mg/kg of body weight from 2 to 6 years, 15 mg/kg from 6 to 10 years, and 10 mg/kg from 10 to 15 years. These assumptions should be prospectively confirmed.The combination of didanosine (ddI), lamivudine (3TC), and efavirenz (EFV) once daily has improved compliance for adults and shown good antiretroviral efficacy (12); moreover, the treatment could be better tolerated in the long term (5, 6, 13). For children, the efficacy and tolerance of this ddI-3TC-EFV combination have not been investigated. The aims of the BURKINAM (ANRS 12103) study, then, were to investigate the pharmacokinetics of EFV, ddI, and 3TC given once daily in children 30 months to 15 years old and to evaluate the efficacy and tolerance of this combination.EFV is metabolized exclusively via CYP2B6 (cytochrome P450 isoenzyme) in the liver (20). Several factors (covariates), such as age (9), duration of treatment (7), or ethnici...

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“…This is consistent with an increase in hepatic activity (including the metabolism of EFV by CYP2B6) between the ages of 1 and 4 years, exceeding adult levels (9).…”

Section: Discussionsupporting

confidence: 62%

“…Several factors (covariates), such as age (9), duration of treatment (7), or ethnicity (8), may affect EFV metabolism. In the present work, a population pharmacokinetic study was performed with African children in order to describe the concentration-time courses of EFV and to study the influence of covariates on EFV pharmacokinetics.…”

mentioning

confidence: 99%

Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?

Hirt

Urien

Mathieu

et al. 2009

Antimicrob Agents Chemother

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“…Although there are no data available regarding the impact of age on hepatic CYP2B6 expression in children and adults, hepatic CYP activity is known to change with age and is often greater in young children (1-4 years old) compared to adults [60]. This is also supported by studies showing that the clearance of CYP substrates including warfarin [61], antipyrine [62], and nelfinavir [63,64] are increased in young children.…”

Section: Age Is An Important Factor That Can Alter the Association Ofsupporting

confidence: 53%

Effect of Host Genetic Variation on the Pharmacokinetics and Clinical Response of Nnrtis

Saitoh

Spector

2007

Future HIV Ther.

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Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been used widely for treating human immunodeficiency virus type 1 (HIV-1) infected patients as a component of highly active antiretroviral therapy (HAART) and for the prevention of mother-to-child transmission (MTCT). Cytochrome P450 (CYP) 2B6 is an important hepatic isoenzyme responsible for the metabolism of NNRTIs including efavirenz and nevirapine. Recent pharmacogenetic studies have shown that CYP2B6 genetic variants alter hepatic CYP2B6 protein expression and function, and the pharmacokinetics of several CYP2B6 substrates. In particular, the CYP2B6-G516T polymorphism in exon 4 affects the pharmacokinetics of efavirenz. Other studies have shown associations of the CYP2B6-G516T genotype with nevirapine pharmacokinetics and central nervous system adverse effects related to efavirenz use. In total, CYP2B6 genetic variants are important determinants of efavirenz and nevirapine pharmacokinetics . Further studies are needed to identify the associations of CYP2B6 genetic variants with the development of NNRTI resistant viruses.

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“…In results not shown in this article, we found a linear relationship of age with improved bioavailability relative to a typical 7 year old. Possible reasons could be that the hepatic enzyme activity between 1 and 4 years exceeds that of adults, and at 7 years it is more comparable to adult activity [55].…”

Section: Discussionmentioning

confidence: 99%

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

Viljoen

Karlsson

Meyers

et al. 2011

Eur J Clin Pharmacol

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Pharmacology considerations for antiretroviral therapy in human immunodeficiency virus (HIV)-infected children

Cited by 23 publications

References 33 publications

Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?

Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?

Effect of Host Genetic Variation on the Pharmacokinetics and Clinical Response of Nnrtis

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

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