Population Pharmacokinetic and Pharmacogenetic Analysis of Nevirapine in Hypersensitive and Tolerant HIV-Infected Patients from Malawi

Abstract

We modeled nevirapine (NVP) pharmacokinetics in HIV-infected Malawian patients to assess the relationship between drug exposure and patient characteristics, genetic polymorphisms, and development of hypersensitivity reaction (HSR). One thousand one hundred seventeen patients were prospectively recruited and followed for 26 weeks with multiple or single serum samples obtained in a subset of patients for NVP quantification. Single nucleotide polymorphisms (SNPs) within CYP2B6 and CYP3A4 genes were typed. Nonlinear mixed effects modeling was utilized to assess the influence of patient characteristics and host genetics on NVP apparent oral clearance (CL/F) and to explore the relationship between NVP CL/F and HSR. Published haplotype distributions were used to simulate NVP concentrations in Caucasians versus Africans. One hundred eighty patients (101 female) were included in the model; 25 experienced HSR. No associations between patient demographics or HSR and NVP CL/F were evident. A significant relationship between CYP2B6 c.983T>C and CYP2B6 c.516G>T and NVP CL/F was observed (P < 0.01). NVP CL/F was reduced by 23% and 36% in patients with CYP2B6 983TT/516TT and 983TC/516GG or GT, respectively, compared to the reference genotype. Simulated exposures suggested similar proportions (13 to 17%) of patients with subtherapeutic NVP among Caucasians and an African population. Influence of CYP2B6 polymorphisms on NVP CL/F in this population is in agreement with other reports. Our data indicate a lack of association between NVP exposure and HSR. Based on these data, dose optimization based solely on ethnicity (without individual gene testing) is unlikely to impact on risk of treatment failure or toxicity even in an African population with high carriage of poor metabolizer mutations.

T Cell–Mediated Hypersensitivity Reactions to Drugs

“…Slow-metabolizer phenotypes for CYP2B6 have been associated with NVP HSR with rash in African populations (65). The CYP2B6 516G → T together with the carriage of HLA-C * 04 in Blacks or HLA-B * 35 and HLA-C * 04 in Asians shows a stronger association with cutaneous phenotypes of NVP HSR than when the alleles are considered alone (16) Slow metabolizers of CYP2B6 have a slower clearance rate for the parent drug (66, 67). A high level of parent drug is likely to facilitate noncovalent binding to HLA, peptide, or TCR.…”

HLA and Delayed Drug-Induced Hypersensitivity

“…HLA-B*35 was also identified as a risk factor for nevirapine-induced DDAR in Caucasians, Thais, and Indians [56,62]. Other alleles described in association with nevirapine-induced allergy/DRESS include HLA-C*04 (in Caucasians, Afro-Americans, Africans, and Han Chinese) [56,63], HLA-C*08 (in Caucasians and Japanese) [64], and the haplotype HLA-C*08-B14 (in Italians) [65]. As several HLA alleles have been described to be associated with nevirapine DDAR, genetic screening for this condition might be difficult to implement [56].…”

“…Although the specific mechanism of drug-HLA interaction largely remains to be discovered, it is known that 12-OH-NVP formation is influenced by the patient's genotype [63]. Moreover, unlike drug exposure, both gender and CD4+ T-cell levels are known to be risk factors for nevirapine DDAR [63].…”

“…Although the specific mechanism of drug-HLA interaction largely remains to be discovered, it is known that 12-OH-NVP formation is influenced by the patient's genotype [63]. Moreover, unlike drug exposure, both gender and CD4+ T-cell levels are known to be risk factors for nevirapine DDAR [63]. It has also been suggested that genes outside the HLA complex [namely noncodifying single nucleotide polymorphisms (SNP) within the CCHCR1 gene] might play an additional role in the development of particular DDAR phenotypes [68].…”

Dual antiviral therapy for HIV and hepatitis C – drug interactions and side effects

“…NVP is primarily metabolized by CYP450 3A4 and 2B6 enzymes. Although CYP2B6 516G>T and CYP2B6 983T>C variant alleles are associated with greater plasma concentrations of NVP, the clinical impact of this finding remains uncertain as an association between greater NVP exposure and toxic effects has not been fully demonstrated [55,56].…”