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Pharmacokinetics of gimatecan, and orally administered camptothecin analogue, in
patients with malignant gliomas
J. G. Supko, L. Alderson, P. Wen, K. Cassidy, S. Pace, M. Obrocea, F. Hochberg
Massachusetts General Hospital, Boston, MA; Rhode Island
Hospital, Providence, RI; Dana Farber Cancer Institute, Boston, MA; Sigma-Tau
Research, Gaithersburg, MD
Background.
Gimatecan (GTN) is a lipophilic camptothecin analogue with
excellent activity against in vivo tumor models when given orally (p.o.).
This report describes the pharmacokinetics (PK) of GTN in a phase I trial in
adults with recurrent malignant gliomas.
Methods.
GTN was given p.o. once a day for 5 days every 4 weeks.
The dose
was independently escalated in patients based upon whether or not enzyme
inducing antiseizure drugs (EIASDs) were used concurrently.
At least 3 patients
were evaluated at each dose level.
Sampling to define GTN plasma profiles for
first and fifth daily doses was performed during cycle 1.
Total GTN (intact
lactone + carboxylate forms) was measured in plasma by HPLC with fluorescence
detection (limit of detection, 1.0 ng/ml).
PK parameters were estimated by
noncompartmental methods and are reported as mean ± SD values.
Results.
PK data are available at 4 doses ranging from 0.33-1.23 mg/m2/day
in 14 non-EIASD patients and from 0.33-1.60 mg/m2/day in 12 patients
receiving EIASDs.
There has been no dose limiting toxicity.
GTN reached a peak
concentration in plasma (Cmax) within 2 h for 90% of all doses (N
= 51).
In the non-EIASD group, GTN had a long terminal half-life of 57 ± 22 h
and an apparent clearance (CL/f) of 1.2 ± 0.9 L/h.
CL/f was not significantly
associated with body surface area suggesting that flat dosing may be
appropriate.
In patients receiving 1.23 mg/m2/day (N = 5),
there was only a 5-fold difference between the trough concentration 24 h after
dose 1 (16 ± 5 ng/ml) and the Cmax for dose 5 (76 ± 21 ng/ml).
The
mean drug accumulation factor was 2.7 ± 0.6 based upon the 24 h area under the
curve for doses 1 and 5.
EIASDs had a marked effect on GTN PK, increasing CL/f
by a factor of 2-10 and decreasing the apparent half-life to a similar
extent.
Conclusions.
Treatment with well tolerated doses of GTN p.o. on a daily x
5 schedule provides prolonged systemic exposure to potentially effective drug
levels.
As with other anticancer agents, EIASDs significantly increased the
clearance of GTN; greater doses will be required to achieve plasma levels that
are comparable to patients not taking EIASDs.
Copyright 2004 American Society of Clinical Oncology All rights
reserved worldwide.
Source: http://www.asco.org/ac/1,1003,_12-002636-00_18-0026-00_19-001617,00.asp
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