TY - JOUR
T1 - Phase I and clinical pharmacological evaluation of aphidicolin glycinate
AU - Sessa, Cristiana
AU - Zucchetti, Massimo
AU - Davoli, Enrico
AU - Califano, Raffaele
AU - Cavalli, Franco
AU - Frustaci, Sergio
AU - Gumbrell, Lindsey
AU - Sulkes, Aaron
AU - Winograd, Benjamin
AU - D'incalci, Maurizio
N1 - Funding Information:
Received September 24, 1990; revised May 2, 1991; accepted May 10, 1991. Supported in part by grants from the Fondazione Ticinese per la Ricerca sul Cancro, Bellinzona, Switzerland, and by ICI Pharmaceuticals, Alderly Park, Cheshire, U.K. C. Sessa, F. Cavalli, L. Gumbrell, Servizio On-cologico, Ospedale San Giovanni, Bellinzona, Switzerland. M. Zucchetti, E. Davoli, R. Califano, M. D'lncalci, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy. S. Frustaci, Centra di Riferimento Oncologico, Aviano (PN), Italy. A. Sulkes, Hadassah Medical Organization, Jerusalem, Israel. B. Winograd, New Drug Development Office, European Organization for Research and Treatment of Cancer, Amsterdam, The Netherlands. *Corrcspondcnce to: Cristiana Sessa, M.D., Ser-vizio Oncologico, Ospedale San Giovanni, 6500 Bellinzona, Switzerland.
PY - 1991/8/21
Y1 - 1991/8/21
N2 - The toxicity profile and the pharmacominetics of ashidicolin glycinate, a water-soluble; ilogue of aphidicolin, have been evaluated in two consecutive phase I clinical studies. In the first study, aphidicolin glycinate was given by 1-hour infusion on for 5 consecutive days, every 3 weeks (daily x 5 study); in the second study, which was planned on the basis of the pharmacokinetic information obtained in the previous study, the drug was given by 24-hour continuous infusion. Treatment was repeated every 3 weeks. In the daily x 5 study, the daily dose was escalated from 12 mg/m2 to the maximum tolerated dose of 2250 mg/m2. Local toxicity was dose limiting. Elimination half-life was 2 ± 0.2 hours (mean ± SE), with aphidicolin being undetectable 6-8 hours after the end of the infusion. In the 24-hour continuous-infusion study, the dose was escalated from 435 mg/m2 to the maximum tolerated dose of 4500 mg/m2. Local toxicity was dose limiting, while other toxic effects were absent. The experimentally determined concentrations at the steady state were in agreement with those predicted on the basis of the available pharmacokinetic data. The targeted concentration at the steady state of 3 μg/mL was achieved at doses greater than or equal to 3000 mg/m2. Twenty-four-hour continuous infusion is the recommended schedule for clinical evaluations of aphidicolin glycinate as the synchronizing agent or in combination with cisplatin. [J Natl Cancer Inst 83: 1160-1164,1991]
AB - The toxicity profile and the pharmacominetics of ashidicolin glycinate, a water-soluble; ilogue of aphidicolin, have been evaluated in two consecutive phase I clinical studies. In the first study, aphidicolin glycinate was given by 1-hour infusion on for 5 consecutive days, every 3 weeks (daily x 5 study); in the second study, which was planned on the basis of the pharmacokinetic information obtained in the previous study, the drug was given by 24-hour continuous infusion. Treatment was repeated every 3 weeks. In the daily x 5 study, the daily dose was escalated from 12 mg/m2 to the maximum tolerated dose of 2250 mg/m2. Local toxicity was dose limiting. Elimination half-life was 2 ± 0.2 hours (mean ± SE), with aphidicolin being undetectable 6-8 hours after the end of the infusion. In the 24-hour continuous-infusion study, the dose was escalated from 435 mg/m2 to the maximum tolerated dose of 4500 mg/m2. Local toxicity was dose limiting, while other toxic effects were absent. The experimentally determined concentrations at the steady state were in agreement with those predicted on the basis of the available pharmacokinetic data. The targeted concentration at the steady state of 3 μg/mL was achieved at doses greater than or equal to 3000 mg/m2. Twenty-four-hour continuous infusion is the recommended schedule for clinical evaluations of aphidicolin glycinate as the synchronizing agent or in combination with cisplatin. [J Natl Cancer Inst 83: 1160-1164,1991]
UR - http://www.scopus.com/inward/record.url?scp=0025742877&partnerID=8YFLogxK
U2 - 10.1093/jnci/83.16.1160
DO - 10.1093/jnci/83.16.1160
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AN - SCOPUS:0025742877
SN - 0027-8874
VL - 83
SP - 1160
EP - 1164
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 16
ER -