Impact of CYP2C19 polymorphism on the pharmacokinetics of nelfinavir in patients with pancreatic cancer

AimThis study evaluated the influence of CYP2C19 polymorphisms on the pharmacokinetics of nelfinavir and its metabolite M8 in patients with pancreatic cancer. MethodsNelfinavir was administered orally to patients for over 10 days. The plasma concentrations of nelfinavir and M8 were measured by HPLC. The genotypes of CYP2C19*1, CYP2C19*2 and CYP2C19*3 were determined by the polymerase chain reaction-restriction fragment length polymorphism method. ResultsPharmacokinetic profiles of nelfinavir and M8 were characterized by wide interindividual variability. The mean C-max of nelfinavir in CYP2C19*1/*1 patients was 3.890.40 (n=3) and 5.12 +/- 0.41 (n=30) mu g ml(-1), while that of CYP2C19*1/*2 patients was 3.60 (n=1) and 6.14 +/- 0.31 (n=5) mu g ml(-1) at the doses of 625 and 1250mg nelfinavir twice daily, respectively. For the M8 metabolite, the mean C-max of CYP2C19*1/*1 patients was 1.06 +/- 0.06 (n=3) and 1.58 +/- 0.27 (n=30) mu g ml(-1), while those of CYP2C19*1/*2 patients were 1.01 (n=1) and 1.23 +/- 0.15 (n=5) mu g ml(-1) at the doses of 625 and 1250mg nelfinavir twice daily, respectively. The area under the plasma concentration-time curve (AUC(0,12 h)) values of nelfinavir for CYP2C19*1/*1 patients were 28.90 +/- 1.27 and 38.90 +/- 4.99 mu g ml(-1)h and for CYP2C19*1/*2 patients, AUC(0,12 h) was 28.20 (n=1) and 40.22 +/- 3.17 (n=5) mu g ml(-1)h at the doses of 625 and 1250mg nelfinavir twice daily, respectively. The C-max of nelfinavir was significantly higher (P <0.05) in CYP2C19*1/*2 patients but there was no statistical difference in AUC(0,12 h). ConclusionCYP2C19*1/*2 genotype modestly affected the pharmacokinetic profiles of nelfinavir and M8 in patients with locally advanced pancreatic cancer.