Background and Objective
Gemcitabine (2′,2’-difluorodeoxycytidine) is an anticancer drug, which is effective against solid tumours, including non-small-cell lung cancer and pancreatic cancer. After gemcitabine is transported into cells by equilibrative and concentrative nucleoside transporters, it is phosphorylated by deoxycytidine kinase (DCK) and further phosphorylated to its active diphosphorylated and triphosphorylated forms. Gemcitabine is rapidly metabolized by cytidine deaminase (CDA) to an inactive metabolite, 2′,2′-difluorodeoxyuridine (dFdU), which is excreted into the urine. Toxicities of gemcitabine are generally mild, but unpredictable severe toxicities such as myelosuppression and interstitial pneumonia are occasionally encountered. The aim of this study was to determine the factors, including genetic polymorphisms of CDA, DCK and solute carrier family 29A1 (SLC29A1 [hENT1]), that alter the pharmacokinetics of gemcitabine in Japanese cancer patients.
Patients and Methods
250 Japanese cancer patients who received 30-minute intravenous infusions of gemcitabine at 800 or 1000mg/m2 in the period between September 2002 and July 2004 were recruited for this study. However, four patients were excluded from the final model built in this study because they showed bimodal concentration-time curves. Two patients who experienced gemcitabine-derived life-threatening toxicities in October 2006 and January 2008 were added to this analysis. One of these patients received 30-minute intravenous infusions of gemcitabine at 454 mg/m2 instead of the usual dose (1000 mg/m2).
Plasma concentrations of gemcitabine and dFdU were measured by high-performance liquid chromatography-photodiode array/mass spectrometry. In total, 1973 and 1975 plasma concentrations of gemcitabine and dFdU, respectively, were used to build population pharmacokinetic models using nonlinear mixed-effects modelling software (NONMEM® version V level 1.1).
Results and Discussion
Two-compartment models fitted well to plasma concentration-time curves for both gemcitabine and dFdU. Major contributing factors for gemcitabine clearance were genetic polymorphisms of CDA, including homozygous CDA*3 [208G>A (Ala70Thr)] (64% decrease), heterozygous *3 (17% decrease) and CDA -31delC (an approximate 7% increase per deletion), which has a strong association with CDA*2 [79A>C (Lys27Gln)], and coadministered S-1, an oral, multicomponent anti-cancer drug mixture consisting of tegafur, gimeracil and oteracil (an approximate 19% increase). The estimated contribution of homozygous CDA*3 to gemcitabine clearance provides an explanation for the life-threatening severe adverse reactions, including grade 4 neutropenia observed in three Japanese patients with homozygous CDA*3. Genetic polymorphisms of DCK and SLC29A1 (hENT1) had no significant correlation with gemcitabine pharmacokinetic parameters. Aging and increased serum creatinine levels correlated with decreased dFdU clearance.
A population pharmacokinetic model that included CDAgenotypes as a covariate for gemcitabine and dFdU in Japanese cancer patients was successfully constructed. The model confirms the clinical importance of the CDA*3 genotype.
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We thank Eli Lilly Japan KK (Kobe, Japan) for kindly providing gemcitabine and dFdU for analytical standards. We thank the patients for participating in this study and Ms Emi Toshiro, Ms Tomoko Chujo, Ms Emiko Usami, Ms Tomoko Matsumura and Ms Mamiko Shimada for assistance in sample collection and processing. We also thank Ms Chie Sudo for secretarial assistance. This study was supported in part by the Program for the Promotion of Fundamental Studies in Health Sciences at the National Institute of Biomedical Innovation [NiBio] (Osaka, Japan) and by a Health and Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare (Tokyo, Japan).
Dr Okusaka reported receiving honoraria from Eli Lilly. The other authors reported no financial disclosures and have no conflicts of interest that are directly relevant to the content of this study.
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Sugiyama, E., Kaniwa, N., Kim, S. et al. Population Pharmacokinetics of Gemcitabine and Its Metabolite in Japanese Cancer Patients. Clin Pharmacokinet 49, 549–558 (2010). https://doi.org/10.2165/11532970-000000000-00000
- Population Pharmacokinetic Model
- Objective Function Value