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.


METHODS
Patients were given i.v. paclitaxel 100 mg/m2 by one-hour infusion followed by gemcitabine 1,500, 1,750 and 2,000 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 (Emax) model.


RESULTS
Paclitaxel pharmacokinetics did not change as a result of dosage escalation of gemcitabine from 1,500 to 2,000 mg/m2. A nonproportional increase in gemcitabine peak plasma levels (Cmax, from 18.56 +/- 4.94 to 40.85 +/- 14.85 microg/ml) and area under the plasma concentration-time curve (AUC, from 9.99 +/- 2.75 to 25.01 +/- 9.87 h x microg/ml) at 1,500 and 2,000 mg/m, respectively, was observed, suggesting the occurrence of saturation kinetics at higher doses. A significant relationship between neutropenia and time of paclitaxel plasma levels > or = 0.05 micromol/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 Cmax, with a predicted effective concentration to induce a 50% decrease of 14.3 microg/ml.


CONCLUSIONS
This study demonstrates the lack of interaction between drugs, the nonproportional pharmacokinetics of gemcitabine at higher doses and the Emax relationship of paclitaxel and gemcitabine with neutrophil and platelet counts, respectively. In addition, gemcitabine 1,500 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.
Fogli
S
S
Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Italy.
Danesi
R
R
De Braud
F
F
De Pas
T
T
Curigliano
G
G
Giovannetti
G
G
Del Tacca
M
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology; D000093542:Gemcitabine
D003841:Deoxycytidine; D017239:Paclitaxel; D000093542:Gemcitabine