Pharmacokinetic and pharmacodynamic study of the combination of docetaxel and topotecan in patients with solid tumors.
OBJECTIVE
The sequence in which chemotherapeutic agents are administered can alter their pharmacokinetics, therapeutic effect, and toxicity. We evaluated the pharmacokinetics and pharmacodynamics of docetaxel and topotecan when coadministered on two different sequences of administration.


METHODS
On cycle 1, docetaxel was administered as a 1-hour infusion at 60 mg/m(2) without filgrastim and at 60, 70, and 80 mg/m(2) with filgrastim on day 1, and topotecan was administered at 0.75 mg/m(2) as a 0.5-hour infusion on days 1 to 4. On cycle 2, topotecan was administered on days 1 to 4, and docetaxel was administered on day 4. Cycles were repeated every 21 days. Blood samples for high-performance liquid chromatography measurement of docetaxel (CL(DOC)) and topotecan (CL(TPT)) total clearance were obtained on day 1 of cycle 1 and day 4 of cycle 2. CL(DOC) and CL(TPT) were calculated using compartmental methods.


RESULTS
Mean +/- SD CL(DOC) in cycles 1 and 2 were 75.9 +/- 79.6 L/h/m(2) and 29.2 +/- 17.3 L/h/m(2), respectively (P: <.046). Mean +/- SD CL(TPT) in cycles 1 and 2 were 8.5 +/- 4.4 L/h/m(2) and 9.3 +/- 3.4 L/h/m(2), respectively (P: >. 05). Mean +/- SD neutrophil nadir in cycles 1 and 2 were 4,857 +/- 6, 738/microL and 2,808 +/- 4,518/microL, respectively (P: =.02).


CONCLUSIONS
Administration of topotecan on days 1 to 4 and docetaxel on day 4 resulted in an approximately 50% decrease in docetaxel clearance and was associated with increased neutropenia.
Zamboni
W C
WC
Program of Molecular Therapeutics and Drug Discovery, University of Pittsburgh Cancer Institute, PA 15213, USA. zamboniwc@msx.upmc.edu
Egorin
M J
MJ
Van Echo
D A
DA
Day
R S
RS
Meisenberg
B R
BR
Brooks
S E
SE
Doyle
L A
LA
Nemieboka
N N
NN
Dobson
J M
JM
Tait
N S
NS
Tkaczuk
K H
KH
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077143:Docetaxel; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010976:Platelet Count / Q000187:drug effects; D011994:Recombinant Proteins; D043823:Taxoids; D019772:Topotecan / Q000008:administration & dosage / Q000493:pharmacokinetics
D011994:Recombinant Proteins; D043823:Taxoids; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel; D019772:Topotecan; D017239:Paclitaxel; D000069585:Filgrastim