Gemcitabine and paclitaxel: pharmacokinetic and pharmacodynamic interactions in patients with non-small-cell lung cancer.
OBJECTIVE
To assess possible pharmacokinetic and pharmacodynamic interactions between gemcitabine and paclitaxel in a phase I/II study in non-small-cell lung cancer (NSCLC) patients.


METHODS
Eighteen patients with advanced NSCLC received the following in a 3-week schedule: gemcitabine 1,000 mg/m(2) (30 minutes, days 1 and 8) and paclitaxel 150 (n = 9) or 200 mg/m(2) (n = 9) before gemcitabine (3 hours, day 1). Plasma pharmacokinetics and pharmacodynamics in mononuclear cells were studied.


RESULTS
Gemcitabine did not influence paclitaxel pharmacokinetics at 150 and 200 mg/m(2) (area under the concentration-time curve [AUC], 7.7 and 8.8 micromol/ L. h, respectively; maximum plasma concentration [C(max)], 3.2 and 4.0 micromol/L, respectively), and paclitaxel did not influence that of gemcitabine (C(max), 30 +/- 3 micromol/L) and 2',2'-difluorodeoxyuridine. Paclitaxel, however, dose-dependently increased the C(max) of gemcitabine triphosphate (dFdCTP), the active metabolite of gemcitabine, from 55 +/- 10 to 106 +/- 16 pmol/10(6) cells.( )No significant difference in the AUC of dFdCTP was observed. Moreover, the gemcitabine-paclitaxel combination significantly increased ribonucleotide levels, most pronounced for adenosine triphosphate (six- to seven-fold). Postinfusion paclitaxel AUC was related to pretreatment hepatic function (bilirubin: r = 0. 79; P <.001) and to the percentage decrease in platelets (r = 0.61; P =.009). The latter was also related to the duration of paclitaxel concentration above 0.1 micromol/L (r = 0.62; P =.007). Gemcitabine C(max )was related to the percentage decrease in platelets (r = 0. 58; P =.01), pretreatment hepatic function (bilirubin: r = 0.77; P <. 001), and to plasma creatinine (r = 0.5; P =.03). The pharmacokinetics and pharmacodynamics were not related to response or survival.


CONCLUSIONS
Gemcitabine and paclitaxel pharmacokinetics were related to the percentage decrease in platelets. Paclitaxel did not affect the pharmacokinetics of gemcitabine, nor did gemcitabine affect the pharmacokinetics of paclitaxel, but paclitaxel increased dFdCTP accumulation. This might enhance the antitumor activity of gemcitabine.
Kroep
J R
JR
Department of Medical Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
Giaccone
G
G
Voorn
D A
DA
Smit
E F
EF
Beijnen
J H
JH
Rosing
H
H
van Moorsel
C J
CJ
van Groeningen
C J
CJ
Postmus
P E
PE
Pinedo
H M
HM
Peters
G J
GJ
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy*; D002478:Cells, Cultured; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D016014:Linear Models; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018709:Statistics, Nonparametric; D000093542:Gemcitabine
D003841:Deoxycytidine; D017239:Paclitaxel; D000093542:Gemcitabine