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
Although some studies have suggested that gemcitabine delivered as a fixed dose rate (FDR) infusion of 10 mg/m2/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/m2 in combination with 75 mg/m2 of cisplatin in advanced non-small-cell lung cancer (NSCLC) patients.
Patients and method
The patients were divided into two groups receiving different initial doses of the drug: 4 patients received 600 mg/m2 gemcitabine 60-min i.v. infusion and 4 patients 1,200 mg/m2 gemcitabine 120-min i.v. infusion both as a FDR of 10 mg/m2/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/m2 120-min i.v. infusion (FDR of 10 mg/m2/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/m2 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.
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.
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.
KeywordsNon-small-cell lung cancer Chemotherapy Cisplatin Gemcitabine Prolonged infusion Pharmacokinetics
- 2.Sandler AB, Nemunaitis J, Denham C, von Pawel J, Cormier Y, Gatzemeier U, Mattson K, Manegold C, Palmer MC, Gregor A, Nguyen B, Niyikiza C, Einhorn LH (2000) Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 18:122–130PubMedGoogle Scholar
- 5.Tempero M, Plunkett W, Ruiz Van Haperen V, Hainsworth J, Hochster H, Lenzi R, Abbruzzese J (2003) Randomized phase II comparison of dose-intense gemcitabine: 30-min infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 21:3402–3408CrossRefPubMedGoogle Scholar
- 7.Poplin E, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O’Dwyer P, Haller D, Catalano P, Cella D, Benson AB III (2009) Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-min infusion) in patients with pancreatic carcinoma E6201: a trial of the eastern cooperative oncology group. J Clin Oncol 27:3778–3785CrossRefPubMedGoogle Scholar
- 8.Caffo O, Binato S, Santo A, Giovannini M, Lucenti A, Centonze M, Zaffaroni M, Zucchetti M, Cartei G, Galligioni E (2003) Prolonged infusion (PI) of gemcitabine (G) in combination with cisplatin (C) in patients with advanced non-small cell lung cancer (NSCLC): preliminary results of a dose-finding and pharmacokinetic (PK) study. In: Proceedings of the 10th world conference on lung cancer. Vancouver, p 230Google Scholar
- 9.Marangon E, Sala F, Caffo O, Galligioni E, D’Incalci M, Zucchetti M (2008) Simultaneous determination of gemcitabine and its main metabolite, dFdU, in plasma of patients with advanced non-small-cell lung cancer by high-performance liquid chromatography–tandem mass spectrometry. J Mass Spectrom 43:216–223CrossRefPubMedGoogle Scholar
- 10.Kirstein MN, Hassan I, Guire DE, Weller DR, Dagit JW, Fisher JE, Remmel RP (2006) High-performance liquid chromatographic method for the determination of gemcitabine and 2′, 2′-difluorodeoxyuridine in plasma and tissue culture media. J Chromatogr B Analyt Technol Biomed Life Sci 835:136–142CrossRefPubMedGoogle Scholar
- 12.Ceribelli A, Gridelli C, De MF, Fabi A, Gamucci T, Cortesi E, Barduagni M, Antimi M, Maione P, Migliorino MR, Giannarelli D, Cognetti F (2003) Prolonged gemcitabine infusion in advanced non-small cell lung carcinoma: a randomized phase II study of two different schedules in combination with cisplatin. Cancer 98:337–343CrossRefPubMedGoogle Scholar
- 13.van Moorsel CJ, Kroep JR, Pinedo HM, Veerman G, Voorn DA, Postmus PE, Vermorken JB, van Groeningen CJ, van der Vijgh WJ, Peters GJ (1999) Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors. Ann Oncol 10:441–448CrossRefPubMedGoogle Scholar
- 14.Patel SR, Gandhi V, Jenkins J, Papadopolous N, Burgess MA, Plager C, Plunkett W, Benjamin RS (2001) Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol 19:3483–3489PubMedGoogle Scholar
- 16.Soo RA, Wang LZ, Tham LS, Yong WP, Boyer M, Lim HL, Lee HS, Millward M, Liang S, Beale P, Lee SC, Goh BC (2006) A multicentre randomised phase II study of carboplatin in combination with gemcitabine at standard rate or fixed dose rate infusion in patients with advanced stage non-small-cell lung cancer. Ann Oncol 17:1128–1133CrossRefPubMedGoogle Scholar
- 18.Javle M, Okazaki T, Evans D, Wolff R, Abbruzzese JL, Li D (2008) Polymorphisms of genes involved in gemcitabine metabolism correlate with prognosis in patients receiving neoadjuvant therapy for pancreatic cancer. J Clin Oncol 26(Suppl):213Google Scholar