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 opportunity in treatment optimization. The present study investigates the pharmacokinetics and pharmacodynamics of paclitaxel and gemcitabine in chemotherapy-naive patients with advanced NSCLC within a phase I study. Patients and methods: Patients were given i.v. paclitaxel 100 mg/m² by one-hour infusion followed by gemcitabine 1500, 1750 and 2000 mg/m² by 30-min administration. Plasma levels of paclitaxel, gemcitabine and its metabolite 2′,2′-difluorodeoxyuridine (dFdU) were determined by high-performance liquid chromatography (HPLC). Concentration-time curves were modeled by compartmental 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 escalation of gemcitabine from 1500 to 2000 mg/m². A nonproportional increase in gemcitabine peak plasma levels (C_max, from 18.56 ± 4.94 to 40.85 ± 14.85 μg/ml) and area under the plasma concentration-time curve (AUC, from 9.99 ± 2.75 to 25.01 ± 9.87 h·μg/ml) at 1500 and 2000 mg/m², respectively, was observed, suggesting the occurrence of saturation kinetics at higher doses. A significant relationship between neutropenia and time of paclitaxel plasma levels ≥ 0.05 μmol/l was observed, with a predicted time of 10.4 h to decrease cell count by 50%. A correlation was also observed between percentage reduction of platelet count and gemcitabine C_max, with a predicted effective concentration to induce a 50% decrease of 14.3 μg/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 platelet counts, respectively. In addition, gemcitabine 1500 mg/m² is the recommended dosage in combination with paclitaxel 100 mg/m² for future phase II studies, due to its predictable kinetic behaviour and less severe thrombocytopenia than expected.