Effect of ADME gene polymorphisms on pemetrexed pharmacokinetics in patients with non-small-cell lung cancer: A prospective study

Abstract

ABSTRACT Background: Pemetrexed is an approved first-line treatment for advanced non-squamous, non-small-cell lung cancer (NSCLC). The pharmacokinetics of pemetrexed is highly variable. Evidence of altered clinical response and toxicity of pemetrexed due to genetic polymorphisms in the folate pathway has generated interest to explore the pharmacogenetic effects on drug exposure and outcomes. Objectives: We evaluated the effect of polymorphisms in the absorption, distribution, metabolism, and elimination (ADME) genes on the pharmacokinetics of pemetrexed in patients with non-squamous NSCLC. Material and Methods: This was a pharmacokinetics-pharmacogenetics correlation study. We enrolled 50 adult patients with non-squamous NSCLC who were planned for treatment with pemetrexed and had adequate hematologic, renal, and hepatic functions. The pharmacokinetics samples were collected after pemetrexed administration, either through a traditional or sparse sampling strategy. The levels were determined using a validated Liquid Chromatography - Tandem Mass Spectrometry (LC-MS/MS) method. Six single nucleotide polymorphisms (SNPs) from the patients’ germline deoxyribonucleic acid (DNA) in the solute carrier family 19 member 1 (SLC19A1), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), and gamma-glutamyl hydrolase (GGH) genes were genotyped using the PharmacoScan array platform. The pharmacokinetics parameters were calculated using non-compartmental analysis (NCA) in Pumas v1.1.0 (Pumas-AI Inc., Baltimore, MD). Mann Whitney U test or Kruskal-Wallis test were used to compare the pharmacokinetics parameters across genotypes. Results: The observed values of systemic clearance, volume of distribution, maximum plasma concentration (Cmax) and total systemic exposure (AUC0-inf) were 2.47 (1.34) L*h-1, 3.76 (3.0) L, 136.8 (61.95) µg/ml and 314.85 (152.56) µg*h*ml-1, respectively. No clinically relevant covariate effect of ADME gene polymorphisms on the pharmacokinetics of pemetrexed was identified. Cmax and AUC0-inf were not significantly different between the wildtype, heterozygous and homozygous populations for any of the SNPs evaluated. Conclusion: ADME gene polymorphisms have no significant effect on the pharmacokinetics of pemetrexed. The evidence is insufficient to support genotype-guided dosing of pemetrexed in patients with non-squamous NSCLC. (Funded by the Indian Council of Medical Research)