Pharmacokinetics and pharmacodynamics of topotecan given on a daily-times-five schedule in phase II clinical trials using a limited-sampling procedure.
Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ring-opened hydroxy acid, is essential for this activity. We performed a pharmacokinetics study as part of phase II clinical trials in patients with various types of solid tumors, giving topotecan at 1.5 mg/m2 per day by 30-min infusion for 5 consecutive days, with courses being repeated every 3 weeks. Previously validated limited-sampling models, using concentration measurements in samples obtained 2 h after infusion, were used to calculate the area under the plasma concentration-time curves (AUCs) for both chemical forms. Samples were obtained from a total of 36 patients over 136 treatment days. The mean AUC of the closed-ring form (AUC(closed)) was 8.74 (range 2.3-16.3 microM min per day, and the mean AUC of the ring-opened form (AUC(open)) was 11.5 (range 3.2-46.0) microM min per day (interpatient variability 34-61%). In each patient the AUC values achieved on the 1st day of administration were similar to and, thus, predictive for those achieved during the following days, with a day-to-day variation of 7.39% being recorded for the AUC(closed) and that of 12.6% for the AUC(open). There was no drug accumulation during the 5 consecutive treatment days of each cycle. However, despite the large interpatient pharmacokinetic variability, the importance of regular drug monitoring on this schedule can be questioned, as the pharmacodynamic variability was relatively small.
van Warmerdam
L J
LJ
Department of Medical Oncology, Antoni van Leeuwenhoekhuis/Netherlands Cancer Institute, Amsterdam, The Netherlands.
Creemers
G J
GJ
Rodenhuis
S
S
Rosing
H
H
de Boer-Dennert
M
M
Schellens
J H
JH
ten Bokkel Huinink
W W
WW
Davies
B E
BE
Maes
R A
RA
Verweij
J
J
Beijnen
J H
JH
D000368:Aged; D000380:Agranulocytosis / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007260:Infusion Pumps; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D013921:Thrombocytopenia / Q000139:chemically induced; D059004:Topoisomerase I Inhibitors; D019772:Topotecan
D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D002166:Camptothecin