Background:Gemcitabine is used for the treatment of several solid tumours and exhibits high inter-individual pharmacokinetic variability. In this study, we explore possible predictive covariates on drug and metabolite disposition.Methods:Forty patients were enrolled. Gemcitabine and dFdU concentrations in the plasma and dFdCTP concentrations in peripheral blood mononuclear cell were measured to 72 h post infusion, and pharmacokinetic parameters were estimated by nonlinear mixed-effects modelling. Patient-specific covariates were tested in model development.Results:The pharmacokinetics of gemcitabine was best described by a two-compartment model with body surface area, age and NT5C2 genotype as significant covariates. The pharmacokinetics of dFdU and dFdCTP were adequately described by three-compartment models. Creatinine clearance and cytidine deaminase genotype were significant covariates for dFdU pharmacokinetics. Rate of infusion of <25 mg m-2 min-1 and the presence of homozygous major allele for SLC28A3 (CC genotype) were each associated with an almost two-fold increase in the formation clearance of dFdCTP.Conclusion:Prolonged dFdCTP systemic exposures (≥72 h) were commonly observed. Infusion rate <25 mg m-2 min-1 and carriers for SLC28A3 variant were each associated with about two-fold higher dFdCTP formation clearance. The impacts of these covariates on treatment-related toxicity in more selected patient populations (that is, first-line treatment, single disease state and so on) are not yet clear.
|Original language||English (US)|
|Number of pages||9|
|Journal||British Journal of Cancer|
|State||Published - Jan 21 2014|
Bibliographical noteFunding Information:
This study was sponsored by a Clinical Scholars Award to MNK, and R01CA132946 to JKL. Analyses of gemcitabine, dFdU and dFdCTP concentrations were conducted by the Clinical Pharmacology Shared Resource, which is supported in part by Cancer Center Support (MN, USA) Grant (5P30 CA77598). We thank the study patient volunteers who donated their valuable time towards the goals of the project. We also thank Linda Kruse, study coordinator, for her outstanding contribution of enrolling the study volunteers and supervising blood sample collection.
- infusion rate
- population pharmacokinetic model