Gemcitabine pharmacokinetics and interaction with paclitaxel in patients with advanced non-small-cell lung cancer.
OBJECTIVE
Gemcitabine administered at a fixed dose rate of 10 mg/m(2) per min has been reported to achieve plasma steady-state concentrations ranging from 10 to 20 microM in patients with acute leukemia. These concentrations have been shown to saturate the intracellular accumulation of the active triphosphate metabolite. We designed this pharmacokinetic study to assess the ability of a fixed dose rate of gemcitabine to achieve the desired steady-state concentration in the absence and presence of paclitaxel in patients with solid tumors.


METHODS
A group of 14 patients with advanced non-small-cell lung cancer received paclitaxel 110 mg/m(2) over 3 h on days 1 and 8 and gemcitabine 800 mg/m(2) over 80 min on days 1 and 8 every 21 days. Patients received gemcitabine alone on cycle (C) 1, day (D) 1. Pharmacokinetic samples were collected at 0, 15, 30, 45, 60 and 80 min during infusion and 0.25, 0.5, 1, 2, 4, 6, and 8 h after infusion on C1D1, C1D8, C2D1, C4D1 and C6D1.


RESULTS
Of 13 patients included in the pharmacokinetic analysis, 61% achieved the desired steady-state concentration (C(ss)) with gemcitabine alone (C1D1), whereas only 0 to 45% of patients achieved the desired C(ss) with paclitaxel and gemcitabine, depending on the treatment cycle. Paclitaxel significantly decreased systemic clearance (Cl(T); P=0.012) and volume of distribution (V(d); P=0.050) and significantly increased C(ss) ( P=0.009). Gemcitabine plasma pharmacokinetic parameters demonstrated great interpatient variability in the absence of paclitaxel (C(ss) 30%, Cl(T) 30%, V(d) 55%). Interpatient and intrapatient variability in gemcitabine pharmacokinetics were not observed when gemcitabine was administered in combination with paclitaxel (P>0.05).


CONCLUSIONS
Gemcitabine plasma pharmacokinetic parameters are significantly altered in the presence of paclitaxel.
School of Pharmacy, CB #7360, Beard Hall, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Stacy S
SS
Shord
Stephanie R
SR
Faucette
Heidi H
HH
Gillenwater
Scott L
SL
Pescatore
Roy L
RL
Hawke
Mark A
MA
Socinski
Celeste
C
Lindley
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000093542:Gemcitabine
D003841:Deoxycytidine; D017239:Paclitaxel; D000093542:Gemcitabine