Quantitative Pharmacogenetics of Cyclophosphamide in Patients with Hematological Malignancies.

A high degree of interindividual variation in cyclophosphamide (CPA) pharmacokinetics was reported in certain cancer patient groups. To better understand the mechanisms underlying the variation in CPA metabolism, the pharmacokinetics of CPA and its active metabolite 4-OH-CPA were estimated in patients with hematological tumors and related to the genotype of CYP2B6, CYP2C9 and CYP2C19. The influence of liver function on CPA metabolism was also evaluated.

Twenty-nine patients with hematological malignancies (MM, ALL or NHL) treated with a conventional CPA dose (1 g/m²) were recruited to this study. Blood samples were collected before, during and after CPA treatment. HPLC was used to measure plasma concentrations of CPA and 4-OH-CPA. Patients were genotyped for the CYP2B6 G516T, CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3 alleles. Serum bilirubin levels were measured before the treatment. Data was analyzed individually and by population pharmacokinetic methods, using non-linear mixed effect modeling. The interindividual variability in exposure to CPA, 4-OHCPA and 4-OH-CPA/CPA was 5.8-, 3.3- and 10.3- fold, respectively. A positive correlation was found between half-lives of CPA and 4-OH-CPA (p<0.05) and there was a significant negative correlation between AUCs of CPA and 4-OH-CPA. In the population analysis the clearance contribution of the CYP2B6 G516T variant allele was about twice the wild type gene while the genotype of CYP2C9 did not influence clearance. A negative correlation was observed between bilirubin level and CPA bioactivation. There is a considerable variation in CPA formation of 4-OH-CPA among patients. The liver function influences CPA metabolism. Presence of the CYP2B6 G516T mutation increases the rate of 4-OH-CPA formation, a substantial variation among patients remain to be explained.