PURPOSE:

This study evaluated the influence of CYP2C19 polymorphism on the pharmacokinetics of nelfinavir and its metabolite M8 in pancreatic cancer patients.

 

METHODS:

Nelfinavir was administered orally to patients for over ten 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.

 

RESULTS:

Pharmacokinetic profiles of nelfinavir and M8 were characterized by wide interindividual variability. The mean Cmax of nelfinavir in CYP2C19*1/*1 patients was 3.89 ± 0.40 (n = 3) and 5.12 ± 0.41 (n = 30) µg/mL, while that of CYP2C19*1/*2 patients was 3.60 (n = 1) and 6.14 ± 0.31 (n = 5) µg/mL at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. For the M8 metabolite, the mean Cmax of CYP2C19*1/*1 patients was 1.06 ± 0.06 (n = 3) and 1.58 ± 0.27 (n = 30) µg/mL, while those of CYP2C19*1/*2 patients was 1.01 (n = 1) and 1.23 ± 0.15 (n = 5) µg/mL at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. The area under the plasma concentration-time curve (AUC0-12h ) values of nelfinavir for CYP2C19*1/*1 patients was 28.90 ± 1.27 and 38.90 ± 4.99 µg/mL∙h, and for CYP2C19*1/*2 patients, AUC0-12h was 28.20 (n = 1) and 40.22 ± 3.17 (n = 5) µg/mL∙h at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. The Cmax of nelfinavir was significantly higher (p <0.05) in CYP2C19*1/*2 patients but there was no statistical difference in AUC0-12h .

 

CONCLUSION:

CYP2C19*1/*2 genotype modestly affected the pharmacokinetic profiles of nelfinavir and M8 in patients with locally advanced pancreatic cancer.