Population pharmacokinetic and pharmacogenetic analysis of nevirapine in hypersensitive and tolerant HIV-infected patients from Malawi.
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.
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
Laura
L
Dickinson
Masautso
M
Chaponda
Daniel F
DF
Carr
Joep J
JJ
van Oosterhout
Johnstone
J
Kumwenda
David G
DG
Lalloo
Munir
M
Pirmohamed
Robert S
RS
Heyderman
Saye H
SH
Khoo
D000328:Adult; D019380:Anti-HIV Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001711:Biotransformation; D044383:Black People; D065702:Cytochrome P-450 CYP2B6; D004342:Drug Hypersensitivity / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006678:HIV; D015658:HIV Infections / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D008295:Malawi; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D044465:White People
D019380:Anti-HIV Agents; D019829:Nevirapine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6