Integration of absorption, distribution, metabolism, and elimination genotyping data into a population pharmacokinetic analysis of nevirapine

Objectives The aim of this analysis was to show the applicability of a newly developed algorithm to assess the influence of genetic variants and other covariates on nevirapine’s drug disposition. The algorithm combines high-throughput genotyping data and nonlinear mixed effects modeling methods. Methods Patients, who participated in the 2NN pharmacokinetic sub study, were reconsented and reenrolled into a clinical trial for genotyping analysis. Overall, 198 single nucleotide polymorphisms located in 45 absorption, distribution, metabolism, and elimination related genes were genotyped using the Illumina BeadArray technology. Data analysis was performed using NONMEM VI and SAS 9.1.3. Results Overall, 1260 nevirapine plasma concentrations were obtained from 271 genotyped patients. Plasma concentration−time profiles of nevirapine were best described by a one-compartment model with auto-induced first-order elimination process. Nevirapine clearance was 19.4% reduced in Asian/Black patients, compared with Caucasian/Hispanic patients. For single nucleotide polymorphism rs3745274 (CYP2B6 516G>T) heterozygous patients (GT) showed a 15.3% reduced clearance; patients with homozygous CYP2B6 516TT alleles showed a 30.6% reduced clearance compared to patients with homozygous 516GG alleles. Patients carrying the homozygote genotype of rs12768009 (CYP2C19 8403AA), highly linked to rs4244285 (CYP2C19*2), showed a 26.8% reduced clearance compared with patients with CYP2C19 8403 AG and GG alleles. Conclusion By integration of high-throughput genotyping data into a pharmacometric analysis of nevirapine, the impact of the CYP2B6 516G>T polymorphism on nevirapine’s exposure was confirmed and quantified. In addition, a new hypothesis with regard to CYP2C19 involvement in nevirapine metabolism has been generated. The analysis presented might help to optimize and individualize the therapy for patients treated with nevirapine to add to their therapeutic benefit.

[1]  H. Akaike.  A new look at the statistical model identification , 1974 .

[2]  Honghao Zhou,et al.  Ethnic Differences in Drug Disposition and Responsiveness , 1991, Clinical pharmacokinetics.

[3]  G R Wilkinson,et al.  The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. , 1994, The Journal of biological chemistry.

[4]  J. Johnson,et al.  Influence of race or ethnicity on pharmacokinetics of drugs. , 1997, Journal of pharmaceutical sciences.

[5]  E. Ette,et al.  Stability and Performance of a Population Pharmacokinetic Model , 1997, Journal of clinical pharmacology.

[6]  P. Dayer,et al.  Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin. , 1998, The Journal of pharmacology and experimental therapeutics.

[7]  T. Macgregor,et al.  Single dose pharmacokinetics and bioavailability of nevirapine in healthy volunteers , 1999, Biopharmaceutics & drug disposition.

[8]  N H Holford,et al.  A procedure for generating bootstrap samples for the validation of nonlinear mixed-effects population models. , 1999, Computer methods and programs in biomedicine.

[9]  T. Macgregor,et al.  Nevirapine Induces Both CYP3A4 and CYP2B6 Metabolic Pathways , 1999 .

[10]  E N Jonsson,et al.  Xpose--an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. , 1999, Computer methods and programs in biomedicine.

[11]  T. Macgregor,et al.  Disposition and biotransformation of the antiretroviral drug nevirapine in humans. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[12]  U. Hofmann,et al.  Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. , 2001, Pharmacogenetics.

[13]  D. Flockhart,et al.  Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism , 2002, Clinical pharmacokinetics.

[14]  T. Bjornsson,et al.  A Review and Assessment of Potential Sources of Ethnic Differences in Drug Responsiveness , 2003, Journal of clinical pharmacology.

[15]  T. Macgregor,et al.  Pharmacokinetic Evaluation and Short-Term Activity of Stavudine, Nevirapine, and Nelfinavir Therapy in HIV-1–Infected Adults , 2004, Journal of acquired immune deficiency syndromes.

[16]  J. Lasker,et al.  CONVERSION OF THE HIV PROTEASE INHIBITOR NELFINAVIR TO A BIOACTIVE METABOLITE BY HUMAN LIVER CYP2C19 , 2004, Drug Metabolism and Disposition.

[17]  E. Niclas Jonsson,et al.  Perl-speaks-NONMEM (PsN) - a Perl module for NONMEM related programming , 2004, Comput. Methods Programs Biomed..

[18]  Julie A. Johnson,et al.  Differences in Drug Pharmacokinetics Between East Asians and Caucasians and the Role of Genetic Polymorphisms , 2004, Journal of clinical pharmacology.

[19]  M. Eichelbaum,et al.  Multiple Novel Nonsynonymous CYP2B6 Gene Polymorphisms in Caucasians: Demonstration of Phenotypic Null Alleles , 2004, Journal of Pharmacology and Experimental Therapeutics.

[20]  B. Gazzard,et al.  Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study , 2004, The Lancet.

[21]  F. van Leth,et al.  Nevirapine and Efavirenz Pharmacokinetics and Covariate Analysis in the 2Nn Study , 2005, Antiviral therapy.

[22]  Amalio Telenti,et al.  Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients , 2005, Pharmacogenetics and genomics.

[23]  M. Eichelbaum,et al.  Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional variants, and possible implications for anti-HIV therapy with efavirenz , 2005, Pharmacogenetics and genomics.

[24]  J. Schellens,et al.  CYP2C9 and CYP2C19 Polymorphic Forms Are Related to Increased Indisulam Exposure and Higher Risk of Severe Hematologic Toxicity , 2007, Clinical Cancer Research.

[25]  V. Natarajan,et al.  Cytochrome P450 2B6 (CYP2B6) G516T influences nevirapine plasma concentrations in HIV‐infected patients in Uganda , 2007, HIV medicine.

[26]  M O Karlsson,et al.  Diagnosing Model Diagnostics , 2007, Clinical pharmacology and therapeutics.

[27]  M Schwab,et al.  Predictive Value of Known and Novel Alleles of CYP2B6 for Efavirenz Plasma Concentrations in HIV‐infected Individuals , 2007, Clinical pharmacology and therapeutics.

[28]  P. Zimmerman,et al.  CYP2B6 983T>C polymorphism is prevalent in West Africa but absent in Papua New Guinea: implications for HIV/AIDS treatment. , 2007, British journal of clinical pharmacology.

[29]  S. Spector,et al.  CYP2B6 genetic variants are associated with nevirapine pharmacokinetics and clinical response in HIV-1-infected children , 2007, AIDS.

[30]  Prosper Chonzi,et al.  High prevalence of the CYP2B6 516G→T(*6) variant and effect on the population pharmacokinetics of efavirenz in HIV/AIDS outpatients in Zimbabwe , 2008, European Journal of Clinical Pharmacology.

[31]  T. Harrer,et al.  Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients. , 2008, The Journal of antimicrobial chemotherapy.

[32]  Thorsten Lehr,et al.  Biosimulation in Clinical Drug Development , 2008 .

[33]  Pinaki Biswas,et al.  Influence of CYP2C19 polymorphism on the pharmacokinetics of nelfinavir and its active metabolite. , 2009, British journal of clinical pharmacology.

[34]  Yuan Chen,et al.  Metabolic Activation of Nevirapine in Human Liver Microsomes: Dehydrogenation and Inactivation of Cytochrome P450 3A4 , 2009, Drug Metabolism and Disposition.

[35]  P. Farndon,et al.  Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17. , 2010, British journal of clinical pharmacology.

[36]  C. Verstuyft,et al.  Population Pharmacokinetic-Pharmacogenetic Study of Nevirapine in HIV-Infected Cambodian Patients , 2010, Antimicrobial Agents and Chemotherapy.

[37]  Thorsten Lehr,et al.  Integration of high-throughput genotyping data into pharmacometric analyses using nonlinear mixed effects modeling , 2010, Pharmacogenetics and genomics.

[38]  M. Pirmohamed,et al.  Haplotype structure of CYP2B6 and association with plasma efavirenz concentrations in a Chilean HIV cohort. , 2010, The Journal of antimicrobial chemotherapy.

[39]  M. Youle,et al.  Integration of population pharmacokinetics and pharmacogenetics: an aid to optimal nevirapine dose selection in HIV-infected individuals , 2011, The Journal of antimicrobial chemotherapy.