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Gemcitabine and Paclitaxel: Pharmacokinetic and Pharmacodynamic Interactions in Patients With Non–Small-Cell Lung Cancer

From the Departments of Medical Oncology and Pulmonology, University Hospital Vrije Universiteit, Amsterdam; and the Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, the Netherlands.

Address reprint requests to Godefridus J. Peters, PhD, Department of Medical Oncology, University Hospital Vrije Universiteit, PO Box 7057, 1007 MB Amsterdam, the Netherlands; email gj.peters{at}azvu.nl

PURPOSE: To assess possible pharmacokinetic and pharmacodynamic interactions between gemcitabine and paclitaxel in a phase I/II study in non–small-cell lung cancer (NSCLC) patients.

PATIENTS AND METHODS: Eighteen patients with advanced NSCLC received the following in a 3-week schedule: gemcitabine 1,000 mg/m² (30 minutes, days 1 and 8) and paclitaxel 150 (n = 9) or 200 mg/m² (n = 9) before gemcitabine (3 hours, day 1). Plasma pharmacokinetics and pharmacodynamics in mononuclear cells were studied.

RESULTS: Gemcitabine did not influence paclitaxel pharmacokinetics at 150 and 200 mg/m² (area under the concentration-time curve [AUC], 7.7 and 8.8 µmol/ L · h, respectively; maximum plasma concentration [C_max], 3.2 and 4.0 µmol/L, respectively), and paclitaxel did not influence that of gemcitabine (C_max, 30 ± 3 µmol/L) and 2',2'-difluorodeoxyuridine. Paclitaxel, however, dose-dependently increased the C_max of gemcitabine triphosphate (dFdCTP), the active metabolite of gemcitabine, from 55 ± 10 to 106 ± 16 pmol/10⁶ cells. No significant difference in the AUC of dFdCTP was observed. Moreover, the gemcitabine-paclitaxel combination significantly increased ribonucleotide levels, most pronounced for adenosine triphosphate (six- to seven-fold). Postinfusion paclitaxel AUC was related to pretreatment hepatic function (bilirubin: r = 0.79; P < .001) and to the percentage decrease in platelets (r = 0.61; P = .009). The latter was also related to the duration of paclitaxel concentration above 0.1 µmol/L (r = 0.62; P = .007). Gemcitabine C_max was related to the percentage decrease in platelets (r = 0.58; P = .01), pretreatment hepatic function (bilirubin: r = 0.77; P < .001), and to plasma creatinine (r = 0.5; P = .03). The pharmacokinetics and pharmacodynamics were not related to response or survival.

CONCLUSION: Gemcitabine and paclitaxel pharmacokinetics were related to the percentage decrease in platelets. Paclitaxel did not affect the pharmacokinetics of gemcitabine, nor did gemcitabine affect the pharmacokinetics of paclitaxel, but paclitaxel increased dFdCTP accumulation. This might enhance the antitumor activity of gemcitabine.

This study was financially supported by the Dutch Cancer Society (grant no. VU 94-753) and by Eli Lilly & Co, International and the Netherlands.

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