Population pharmacokinetic and pharmacogenetic analysis of nevirapine in hypersensitive and tolerant HIV‐infected patients from Malawi

Dickinson, Laura; Chaponda, Mas; Carr, Daniel F.; Oosterhout, JJ van; Kumwenda, Johnstone; Lalloo, DG; Heyderman, Robert S.; Khoo, SH

doi:10.1186/1758-2652-13-s4-p181

Cited by 3 publications

(9 citation statements)

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“…Two single nucleotide polymorphisms (SNPs) in the CYP2B6 gene, c.516G>T (rs3745274) and c.983T>C (rs28399499), have been shown to affect CYP2B6 enzyme activity and NVP plasma concentration (Dickinson et al, 2014;Hoffman et al, 2001). However, this has yet to be demonstrated for the Zimbabwean population.…”

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confidence: 99%

“…However, this has yet to be demonstrated for the Zimbabwean population. Both variants, one in exon 4, CYP2B6 c.516T (p. 172H), and the second in exon 7, CYP2B6 c.983C (p. 328Thr), have been associated with a significant loss of function of the resultant protein, and therefore higher levels of NVP compared to the alternative alleles (Code et al, 1997;Dickinson et al, 2014;Gounden et al, 2010;Haas et al, 2009;Hofmann et al, 2008;Rotger et al, 2007).…”

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confidence: 99%

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Effects ofCYP2B6andCYP1A2Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients

Mhandire

Lacerda

Castel

et al. 2015

OMICS: A Journal of Integrative Biology

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The extremely high prevalence of HIV/AIDS in sub-Saharan Africa and limitations of current antiretroviral medicines demand new tools to optimize therapy such as pharmacogenomics for person-toperson variations. African populations exhibit greater genetic diversity than other world populations, thus making it difficult to extrapolate findings from one population to another. Nevirapine, an antiretroviral medicine, displays large plasma concentration variability which adversely impacts therapeutic virological response. This study, therefore, aimed to identify sources of variability in nevirapine pharmacokinetics and pharmacodynamics, focusing on genetic variation in CYP2B6 and CYP1A2. Using a cross-sectional study design, 118 HIV-infected adult Zimbabwean patients on nevirapine-containing highly active antiretroviral therapy (HAART) were characterized for three key functional single nucleotide polymorphisms (SNPs), CYP2B6 c.516G>T (rs3745274), CYP2B6 c.983T>C (rs28399499), and CYP1A2 g.-163C>A (rs762551). We investigated whether genotypes at these loci were associated with nevirapine plasma concentration, a therapeutic biomarker, and CD4 cell count, a biomarker of disease progression. CYP2B6 and CYP1A2 were chosen as the candidate genes based on reports in literature, as well as their prominence in the metabolism of efavirenz, a drug in the same class with nevirapine. Nevirapine plasma concentration was determined using LC-MS/MS. The mean nevirapine concentration for CYP2B6 c.516T/T genotype differed significantly from that of 516G/G ( p < 0.001) and 516G/T ( p < 0.01) genotypes, respectively. There were also significant differences in mean nevirapine concentration between CYP2B6 c.983T > C genotypes ( p = 0.04). Importantly, the CYP1A2 g.-163C>A SNP was significantly associated with the pharmacodynamics endpoint, the CD4 cell count ( p = 0.012). Variant allele frequencies for the three SNPs observed in this Zimbabwean group were similar to other African population groups but different to observations among Caucasian and Asian populations. We conclude that CYP2B6 c.516G>T and CYP2B6 c.983T>C could be important sources of nevirapine pharmacokinetic variability that could be considered for dosage optimization, while CYP1A2 g.-163C>A seems to be associated with HIV disease progression. These inter-and intra-population pharmacokinetic and pharmacodynamics differences suggest that a single prescribed dosage may not be appropriate for the treatment of disease. Further research into a personalized nevirapine regimen is required.

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confidence: 99%

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confidence: 99%

Effects ofCYP2B6andCYP1A2Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients

Mhandire

Lacerda

Castel

et al. 2015

OMICS: A Journal of Integrative Biology

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“…82 These findings add to a growing number of observations showing that multiple processes including pharmacological and immunological mechanisms contribute to ADRs that may be mediated by the parent drug, and that dose dependency is likely a key feature of both on-target and off-target ADRs ( Figure 1). [85][86][87][88][89] Drug-specific models: allopurinol Allopurinol is a xanthine oxidase inhibitor that is used to treat hyperuricemia and is associated with an IM-ADR of variable, but primarily cutaneous, phenotype in approximately 2% of patients who initiate therapy. In 2005, it was demonstrated that the HLA-B*58:01 genotype is associated with allopurinol-induced SJS/TEN and DRESS in persons of Han Chinese ancestry (100% negative predictive value, 3% positive predictive value).…”

Section: Drug-specific Models: Abacavirmentioning

confidence: 99%

Evolving models of the immunopathogenesis of T cell–mediated drug allergy: The role of host, pathogens, and drug response

2015

Journal of Allergy and Clinical Immunology

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Immune-mediated adverse drug reactions (IM-ADRs) are an underrecognized source of preventable morbidity, mortality, and cost. Increasingly, genetic variation in the HLA loci is associated with risk of severe reactions, highlighting the importance of T-cell immune responses in the mechanisms of both B-cell mediated and primary T-cell mediated IM-ADRs. In this review, we summarize the role of host genetics, microbes and drugs in the development of IM-ADRs, expand upon the existing models of IM-ADR pathogenesis to address multiple unexplained observations, discuss the implications of this work in clinical practice today, and describe future applications for pre-clinical drug toxicity screening, drug design, and development.

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“…These correlations have led to recommendations to reduce the EFV dosage in order to prevent occurrence of the adverse drug effects [18,24]. Individuals with the CYP2B6*6 allele have also been shown to have a significant increase in nevirapine plasma concentrations, which has been associated with immunologic response [19]. The use of singledose NVP to prevent perinatal vertical transmission has been reported to have pro¬longed exposures in women with the CYP2B6*6 allele, which greatly increases the risk of developing resistance mutations to NVP [25].…”

Section: Introductionmentioning

confidence: 99%

“…Likewise, studies have also been done in African populations to evaluate the clinical implications of the CYP2B6*6 allele in the use of efavirenz [15][16][17][18], and nevirapine [19][20][21]. CYP2B6*6 has been associated with higher efavirenz plasma concentrations due to lower clearance rates, which may lead to CNS side effects [22,23].…”

Section: Introductionmentioning

confidence: 99%

CYP2B6*6 Screening; Potential Benefits and Challenges in HIV Therapy in Sub-Saharan Africa

Dhoro¹

2017

J Clin Cell Immunol

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CYP2B6*6 genotyping appears to be a promising approach towards the prediction of efavirenz toxicity and risk of developing resistant mutations to nevirapine. The use of cost-effective technologies to screen for the allele may therefore become part of routine clinical practice, for which benefits in terms of cost reduction for governments and patients are evident. However, pharmacogenomics has not yet lived up to its hype and benefits in both the developed and developing worlds in particular sub-Saharan Africa where access to basic healthcare services is limited. Although numerous reports have advocated for the implementation of CYP2B6*6-guided drug therapy in HIV patients receiving efavirenz or nevirapine, this has not been effected yet. The reasons require both practical and clinical considerations.

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Population pharmacokinetic and pharmacogenetic analysis of nevirapine in hypersensitive and tolerant HIV‐infected patients from Malawi

Abstract: 7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

Cited by 3 publications

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Effects ofCYP2B6andCYP1A2Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients

Effects ofCYP2B6andCYP1A2Genetic Variation on Nevirapine Plasma Concentration and Pharmacodynamics as Measured by CD4 Cell Count in Zimbabwean HIV-Infected Patients

Evolving models of the immunopathogenesis of T cell–mediated drug allergy: The role of host, pathogens, and drug response

CYP2B6*6 Screening; Potential Benefits and Challenges in HIV Therapy in Sub-Saharan Africa

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