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: 3.02). 01/2008; 13(6):779-87.
Source: PubMed


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.

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Available from: Henriëtte J Scherpbier, Oct 07, 2014
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    • "Similarly, an EFV pharmacokinetics study in Ugandan adults suggested that a daily EFV dose of 300 mg may be adequate for individuals carrying the CYP2B6 c.516 T/T genotype [47]. Ter Heine et al. [28], showed that children carrying the CYP2B6 c516G/G genotype had a 50–70 % probability of developing sub-therapeutic EFV concentrations, pointing towards the need for dose optimisation in both adults and children. Cases 1, 2 and 3, as compared to case 4, carried not only the CYP2B6 c. 516G > T SNP but additional heterozygous SNP's conferring impaired CYP2B6 activity resulting in higher plasma EFV concentrations. "
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    ABSTRACT: Background Efavirenz, widely used as part of antiretroviral drug regimens in the treatment of paediatric human immunodeficiency virus infection, has central nervous system side effects. We describe four children presenting with serious, persistent central nervous system adverse events who were found to have elevated plasma efavirenz concentrations as a result of carrying CYP2B6 single nucleotide polymorphisms, known to play a role in the metabolism of EFV. None of the children had a CYP2B6 wildtype haplotype. We believe this is the first case of cerebellar dysfunction associated with efavirenz use to be described in children. Case presentation Four black African children, between the ages of 4 and 8 years presenting between 1 and 20 months post-efavirenz initiation, are described. Cerebellar dysfunction, generalised seizures and absence seizures were the range of presenting abnormalities. Plasma efavirenz levels ranged from 20-60 mg/L, 5–15 times the upper limit of the suggested reference range. All abnormal central nervous system manifestations abated after efavirenz discontinuation. Conclusion Efavirenz toxicity should always be considered in human immunodeficiency virus-infected children with unexplained central nervous system abnormalities. Our findings further our understanding of the impact of genetic variants on antiretroviral pharmacokinetics in children across various ethnic groups. Screening for potential EFV-toxicity based on the CYP2B6 c.516 SNP alone, may not be adequate.
    Preview · Article · Dec 2015 · BMC Infectious Diseases
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    • "516GG (wild-type) genotype had a risk of sub-therapeutic EFV plasma concentration (Rodriguez-Novoa et al., 2005; ter Heine et al., 2008); the possible explanation could be due to the presence of 785A>G polymorphism, not assessed in both studies. Furthermore, also the CYP2B6*16 allele contains the 785A>G polymorphism (together with 983T>C) and the high EFV plasma concentration of carriers of *16 allele (Wang et al., 2006) is mostly due to the presence of the 983T>C polymorphism. "
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    ABSTRACT: The prescription of patients' tailored anti-infectious treatments is the ultimate goal of pharmacogenetics/genomics applied to antimicrobial treatments, providing a basis for personalized medicine. Despite the efforts to screen Africans for alleles underlying defective metabolism for a panel of different drugs, still more research is necessary to clarify the interplay between host genetic variation and treatments' response. HIV is a major infectious disease in sub-Saharan African countries, and the main prescribed anti-HIV combination therapy includes efavirenz (EFV) or nevirapine (NVP). The two drugs are both mainly metabolised by cytochrome P450 2B6 liver enzyme (CYP2B6). Defective variants of CYP2B6 gene, leading to higher drug exposure with subsequent possible side effects and low compliance, are well known. However, little is known about CYP2B6 alleles in Cameroon where only one study was done on this subject. The main objective of the present work is to assess, in a subset of HIV-exposed subjects from Dschang in West Cameroon, the prevalence of two SNPs in the CYP2B6 gene: 516G>T (rs3745274) and 983T>C (rs28399499), both associated to a defective EFV and NVP metabolism. We analyzed 168 DNA samples collected during two cross-sectional surveys performed in Dschang, West Cameroon. In the population studied the observed allele frequencies of 516G>T and 983T>C were 44.35% (95%CI, 36.84-51.86%) and 12.80% (95%CI, 7.75-17.85%), respectively. Moreover, concerning the CYP2B6 expected phenotypes, 28.57% of the population showed a poor metaboliser phenotype, while 27.38% and 44.05% showed an extensive (wild-type) and an intermediate metaboliser phenotype, respectively. Here we found that an important fraction of the subjects is carrying EFV/NVP poor metaboliser alleles. Our findings could help to improve the knowledge about the previewed efficacy of anti-HIV drug therapy in Cameroon. Finally, we designed a new method of detection for the 983T>C genetic variation that can be applied in resource-limited laboratories. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Aug 2015 · Infection Genetics and Evolution
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    • "In the first work ever assessing the encapsulation of an anti-HIV drug within polymeric micelles to improve its oral bioavailability, we thoroughly investigated the capacity of a broad variety of pristine and chemically modified PEOePPO micelles [34] [35] to host and release EFV. We have also developed a concentrated taste-masked formulation with high physicochemical stability [36] that would enable easier dose adjustment and swallowing [37]. The aqueous solubility was increased more than 8400 times (up to 34 mg/mL) [38]. "
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    ABSTRACT: Aiming to improve the pediatric pharmacotherapy of the human immunodeficiency virus (HIV) infection, our group has recently developed a concentrated formulation of the first-line antiretroviral efavirenz by means of encapsulation within polymeric micelles. The aqueous solubility of the drug was increased more than 8400 times (up to 34mg/mL) and preliminary preclinical data suggested the significantly greater oral bioavailability with respect to an extemporaneous suspension and an oleous solution (similar to the only "commercially available" pediatric formulation). As the preamble to a bioequivalence trial to evaluate the micellar system in adult healthy volunteers, the present work investigated the effect of parameters such as dose per body weight and drug concentration on the oral pharmacokinetics of the drug. The non-linear pharmacokinetics of the drug was confirmed for all the formulations. Despite the drug concentration and dose, micelles consistently resulted in significantly greater absorption rates, PK parameters increasing up to 3-fold. For example, C(max) values increased from 687, 1789 and 2657ng/mL for the oily system to 1145, 2856 and 7056ng/mL for the micellar one, for EFV doses between 20 and 80mg/kg. Data clearly showed that the smaller the micellar size, the higher the bioavailability attained. The effect of micellar size was also assessed. In addition, a comparison between in vitro dissolution rates of EFV for the different micelles and AUC values suggested that micelles releasing faster in vitro lead to a less pronounced absorption in vivo. These findings would suggest the involvement of additional absorption mechanisms.
    Full-text · Article · Mar 2011 · Biomaterials
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