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

• Published in: British journal of clinical pharmacology 2015-08, Vol.80 (2), p.267-275
• Main Authors: Kattel, Krishna, Evande, Ruby, Tan, Chalet, Mondal, Goutam, Grem, Jean L., Mahato, Ram I.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Area Under Curve; CYP2C19; Cytochrome P-450 CYP2C19 - genetics; Dose-Response Relationship, Drug; Female; genotype; Humans; Male; metabolite; Middle Aged; nelfinavir; Nelfinavir - administration & dosage; Nelfinavir - blood; Nelfinavir - pharmacokinetics; Nelfinavir - therapeutic use; Pancreatic Neoplasms - blood; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - enzymology; Pharmacokinetics; Polymorphism, Restriction Fragment Length
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.12620

Aim This study evaluated the influence of CYP2C19 polymorphisms on the pharmacokinetics of nelfinavir and its metabolite M8 in patients with pancreatic cancer. Methods Nelfinavir 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. 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–1, while that of CYP2C19*1/*2 patients was 3.60 (n = 1) and 6.14 ± 0.31 (n = 5) µg ml–1 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–1, while those of CYP2C19*1/*2 patients were 1.01 (n = 1) and 1.23 ± 0.15 (n = 5) µg ml–1 at the doses of 625 and 1250 mg 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 µg 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) µg ml–1·h at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. The Cmax of nelfinavir was significantly higher (P