title: Phase I and clinical pharmacological evaluation of aphidicolin glycinate.
abstract: The toxicity profile and the pharmacokinetics of aphidicolin glycinate, a water-soluble analogue of aphidicolin, have been evaluated in two consecutive phase I clinical studies. In the first study, aphidicolin glycinate was given by 1-hour infusion 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 micrograms/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.
authors.affiliation: Servizio Oncologico, Ospedale San Giovanni, Bellinzona, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Sessa
authors.forename: M
authors.initials: M
authors.lastname: Zucchetti
authors.forename: E
authors.initials: E
authors.lastname: Davoli
authors.forename: R
authors.initials: R
authors.lastname: Califano
authors.forename: F
authors.initials: F
authors.lastname: Cavalli
authors.forename: S
authors.initials: S
authors.lastname: Frustaci
authors.forename: L
authors.initials: L
authors.lastname: Gumbrell
authors.forename: A
authors.initials: A
authors.lastname: Sulkes
authors.forename: B
authors.initials: B
authors.lastname: Winograd
authors.forename: M
authors.initials: M
authors.lastname: D'Incalci
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016590:Aphidicolin / Q000031:analogs & derivatives*; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors*; D004224:Diterpenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D016590:Aphidicolin; C068151:aphidicolin glycinate; D004257:DNA Polymerase II