Article

A pharmacokinetic and pharmacogenetic study of efavirenz in children: dosing guidelines can result in subtherapeutic concentrations.

Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, the Netherlands.
Antiviral therapy (Impact Factor: 3.14). 01/2008; 13(6):779-87.
Source: PubMed

ABSTRACT Our main objectives were to study the population pharmacokinetics of efavirenz and to explore the adequacy of dosing guidelines.
A total of 33 HIV-1-infected patients were recruited from the Emma Children's Hospital (Amsterdam, the Netherlands). Gender, age, drug formulation, the presence of the c.516G>T polymorphism in the CYP2B6 gene and the quantitation of liver enzymes alanine aminotransferase and aspartate aminotransferase at baseline were collected. A non-linear mixed effect pharmacokinetic model was developed.
CYP2B6 genotype and drug formulation significantly influenced efavirenz pharmacokinetics. Clearance was 29.7% lower in children carrying the CYP2B6-516-G/T genotype compared with children carrying the G/G genotype. Relative bioavailiability of the oral liquid compared with tablets or capsules was 46.6%. Children carrying the CYP2B6-516-G/G genotype had a 50-70% probability of developing a subtherapeutic trough level of efavirenz and only 1-3% probability of developing a trough level >4 mg/l. To reduce the probability of developing a subtherapeutic trough concentration, we propose to give an adult efavirenz dose to children weighing > or =25 kg and to allometrically scale doses for other weight levels a priori. The dose of the oral solution should be twice the dose of capsules.
Population pharmacokinetics of efavirenz in children were adequately described. Current dosing guidelines can result in subtherapeutic concentrations in children carrying the CYP2B6-516-G/G genotype and with the liquid formulation. A priori dose adaptations in the paediatric population seem feasible and need prospective validation.

0 Followers
 · 
127 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: A multitude of antiretroviral drug formulations are now available for HIV-infected adults and children. These formulations include individual and co-formulated drugs, many of which are also supplied in generic versions. Many antiretroviral drugs have a low aqueous solubility and poor bioavailability. Drug formulation can significantly affect bioavailability, and given the increasing number of new formulations and drug combinations, it is important to be aware that formulation can influence the pharmacokinetics of antiretroviral drugs. Areas covered: This review provides an overview of studies assessing the pharmacokinetics of different antiretroviral drug formulations in adults and children, including fixed-dose combinations. For some antiretroviral drugs, differences in pharmacokinetics have been described, with largest differences in exposure when a liquid formulation is compared to a tablet or capsule formulation. Biopharmaceutical properties of antiretroviral drugs relevant to bioavailability are discussed. Expert opinion: Antiretroviral drug formulations and their excipients can significantly impact drug exposure. However, this is not yet fully recognized. It is important to realize that children use different formulations than adults. Effort should be made to ensure that adequate drug exposures are achieved to treat HIV-infected children. In addition, manipulation of drug formulations may lead to differences in pharmacokinetics.
    Expert Opinion on Drug Metabolism &amp Toxicology 05/2014; DOI:10.1517/17425255.2014.925879 · 2.93 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim: Antiretroviral treatment implies a high cost to the healthcare system. The aim of this study was to evaluate the clinical and economic impact of efavirenz (EFV) dose adjustment by monitoring plasma concentrations and pharmacogenetic analysis of the 516G>T CYP2B6 polymorphism. Materials & methods: One hundred and ninety HIV patients treated with EFV were studied. Plasma EFV concentrations were measured by HPLC with ultraviolet detection, and pharmacogenetic analysis was performed by Real Time (RT)-PCR. Results: One hundred and ninety patients initially treated with a standard dose of EFV (600 mg/day) were studied. In 31 (16.3%) patients, EFV dose was reduced. A total of 87.1% of patients were heterozygous/homozygous carriers (GT/TT). CD4(+) count increased while the minimum steady-state plasma concentration and adverse effects decreased significantly after dose adjustment. Considering only the dose reduction, the adjustments accounted for a saving of 43,539 €/year. Conclusion: The individualization of EFV dosage guided by genotyping 516G>T CYP2B6 and therapeutic drug monitoring could increase the efficiency of EFV use in antiretroviral treatment. Original submitted 28 November 2013; Revision submitted 10 March 2014.
    Pharmacogenomics 05/2014; 15(7):997-1006. DOI:10.2217/pgs.14.48 · 3.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this analysis was to create a pharmacometric model of efavirenz developmental pharmacokinetics and pharmacogenetics in HIV-infected children. Data consisted of 3,172 plasma concentrations from 96 HIV-1 infected children who participated in the Pediatric AIDS Clinical Trials Group 382 (PACTG382) study. Analyses were performed using NONMEM and the impact of body weight, age, race, sex, formulation, liver function, CYP2B6-G516T and MDR1-C3435T polymorphisms was assessed. A one-compartment model using weight-based allometry on oral clearance and apparent volume of distribution adequately described the data. A sigmoid Emax maturation model demonstrated an increase in oral clearance with age to reach 90% of its mature level by the age of 9 months. The liquid formulation bioavailability relative to the capsule was found to increase with age to reach 90% of its mature value by the age of 8 years. The CYP2B6-G516T polymorphism decreased oral clearance while the MDR1-C3435T polymorphism demonstrated no effect.
    Antimicrobial Agents and Chemotherapy 10/2013; 58(1). DOI:10.1128/AAC.01738-13 · 4.45 Impact Factor