Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors

Purpose: To determine possible schedule dependent pharmacokinetic and pharm acodynamic interactions between gemcitabine (2',2'-difluorodeoxycytidine, d FdC) and cisplatin (cis-diammine-dichloroplatinum, CDDP) in patients with a dvanced stage solid tumors in a phase I trial. Patients and methods: A total of 33 patients with advanced stage solid tumo rs were treated with gemcitabine (30-min infusion, 800 mg/m(2)) and cisplat in (one-hour infusion, 50 mg/m2). Sixteen patients had a four-hour interval between gemcitabine (days 1, 8, 15) and cisplatin (days 1 and 8), followed by the reverse schedule and seventeen patients had a 24-hour interval betw een gemcitabine (days 1, 8, 15) and cisplatin (days 2 and 9), followed by t he reverse schedule. Gemcitabine and cisplatin pharmacokinetics were measur ed in plasma and white blood cells (WBC), isolated from blood samples taken at several time points after the start of treatment. Results: A four-hour time interval between both agents did not reveal major differences in plasma pharmacokinetics of gemcitabine, dFdU (deaminated ge mcitabine) and platinum (Pt), and of gemcitabine-triphosphate (dFdCTP) accu mulation and Pt-DNA adduct formation in WBC between the two different seque nces of gemcitabine and cisplatin. In the patients treated with the 24-hour interval, cisplatin before gemcitabine did not significantly change peak g emcitabine levels and the AUC of plasma dFdU, but tended to increase dFdCTP AUC in WBC 1.5-fold (P < 0.06). Gemcitabine before cisplatin decreased the plasma AUC of Pt 2.1-fold (P = 0.03). No significant differences in Pt-DNA adduct levels in WBC were found, although gemcitabine before cisplatin ten ded to increase the 24-hour retention of Pt-DNA adducts. Creatinine clearan ce on day 28 was related to the peak plasma levels of total Pt (linear regr ession coefficient (r) = 0.47, P = 0.02, n = 26). Furthermore, the increase in the Pt-GG to Pt-AG ratio 24 hours after cisplatin treatment was related to the overall response of patients (r = 0.89, P < 0.01, n = 8). Conclusions: Of all schedules the treatment of patients with cisplatin 24 h ours before gemcitabine led to the highest dFdCTP accumulation in WBC and t otal Pt levels in plasma. These characteristics formed the basis for furthe r investigation of this schedule in a phase II clinical study.