Pharmacokinetic study of gemcitabine, given as prolonged infusion at fixed dose rate, in combination with cisplatin in patients with advanced non-small-cell lung cancer.
BACKGROUND
Although some studies have suggested that gemcitabine delivered as a fixed dose rate (FDR) infusion of 10 mg/m(2)/min could be more effective than when administered as the standard 30-min infusion, the available pharmacokinetic data are still too limited to draw definitive conclusions. This study is aimed to investigate the plasmatic and intracellular pharmacokinetics of gemcitabine given as FDR at doses of 600 and 1,200 mg/m(2) in combination with 75 mg/m(2) of cisplatin in advanced non-small-cell lung cancer (NSCLC) patients.


METHODS
The patients were divided into two groups receiving different initial doses of the drug: 4 patients received 600 mg/m(2) gemcitabine 60-min i.v. infusion and 4 patients 1,200 mg/m(2) gemcitabine 120-min i.v. infusion both as a FDR of 10 mg/m(2)/min on days 1 and 8 of a 21-day cycle (at first cycle). At the second cycle, all patients were treated with gemcitabine at 1,200 mg/m(2) 120-min i.v. infusion (FDR of 10 mg/m(2)/min) on days 1 and 8 of a 21-day cycle. At each cycle, gemcitabine was administered alone on day one, and in combination with 75 mg/m(2) of cisplatin on day 8. Plasmatic and intracellular pharmacokinetic analyses were performed on blood samples collected at defined time points before, during and after gemcitabine infusion.


RESULTS
The plasmatic pharmacokinetic parameters were clearly different when the patients received a higher gemcitabine dose in the second cycle compared to the lower dose of the first course; in the same time, the intracellular drug levels were not modified. Comparing the pharmacokinetic parameters of different patients treated at different dose levels, the results appeared to be quite similar.


CONCLUSIONS
A substantially higher accumulation of metabolites in peripheral blood mononuclear cells was observed when the longer infusion time was employed, suggesting a pharmacological advantage for this treatment schedule.
Caffo
Orazio
O
Medical Oncology Department, Santa Chiara Hospital, Trento, Italy. orazio.caffo@apss.tn.it
Fallani
Stefania
S
Marangon
Elena
E
Nobili
Stefania
S
Cassetta
Maria Iris
MI
Murgia
Viviana
V
Sala
Federica
F
Novelli
Andrea
A
Mini
Enrico
E
Zucchetti
Massimo
M
Galligioni
Enzo
E
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous / Q000379:methods; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis; D016896:Treatment Outcome; D000093542:Gemcitabine
D003841:Deoxycytidine; D002945:Cisplatin; D000093542:Gemcitabine