Drug distribution and pharmacokinetic/pharmacodynamic relationship of paclitaxel and gemcitabine in patients with non-small-cell lung cancer

Background: Gemcitabine and paclitaxel are two of the most active agents in non-small-cell lung cancer (NSCLC), and pharmacologic investigation of the combination regimens including these drugs may offer a valuable opportunit y in treatment optimization. The present study investigates the pharmacokin etics and pharmacodynamics of paclitaxel and gemcitabine in chemotherapy-na ive patients with advanced NSCLC within a phase I study. Patients and methods:Patients were given i.v. paclitaxel 100 mg/m(2) by one -hour infusion followed by gemcitabine 1500, 1750 and 2000 mg/m(2) by 30-mi n administration. Plasma levels of paclitaxel, gemcitabine and its metaboli te 2',2'-difluorodeoxyuridine (dFdU) were determined by high-performance li quid chromatography (HPLC). Concentration-time curves were modeled by compa rtmental and non-compartmental methods and pharmacokinetic/pharmacodynamic (PK/PD) relationships were fitted according to a sigmoid maximum effect (E- max) model. Results: Paclitaxel pharmacokinetics did not change as a result of dosage e scalation of gemcitabine from 1500 to 2000 mg/m(2). A nonproportional incre ase in gemcitabine peak plasma levels (C-max, from 18.56 +/- 4.94 to 40.85 +/- 14.85 mug/ml) and area under the plasma concentration-time curve (AUC, from 9.99 +/- 2.75 to 25.01 +/- 9.87 h.mug/ml) at 1500 and 2000 mg/m(2), re spectively, was observed, suggesting the occurrence of saturation kinetics at higher doses. A significant relationship between neutropenia and time of paclitaxel plasma levels greater than or equal to0.05 mu mol/l was observe d, with a predicted time of 10.4 h to decrease cell count by 50%. A correla tion was also observed between percentage reduction of platelet count and g emcitabine C-max, with a predicted effective concentration to induce a 50% decrease of 14.3 mug/ml. Conclusion: This study demonstrates the lack of interaction between drugs, the nonproportional pharmacokinetics of gemcitabine at higher doses and the E-max relationship of paclitaxel and gemcitabine with neutrophil and plate let counts, respectively. In addition, gemcitabine 1500 mg/m(2) is the reco mmended dosage in combination with paclitaxel 100 mg/m(2) for future phase II studies, due to its predictable kinetic behaviour and less severe thromb ocytopenia than expected.