title: Phase II dose escalation study of caspofungin for invasive Aspergillosis.
abstract: Our objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the same non-hematological treatment-related adverse event of grade ≥ 4 in 2 of 8 patients or ≥ 3 in 4 of 8 patients in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies) received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5 days. Plasma pharmacokinetics were linear across the investigated dosages and followed a two-compartment model, with weight as the covariate on clearance and sex as the covariate on central volume of distribution. Simulated peak plasma concentrations at steady state ranged from 14.2 to 40.6 mg/liter (28%), trough concentrations from 4.1 to 11.8 mg/liter (58%), and area under the concentration-time curve from 175 to 500 mg/liter/h (32%) (geometric mean, geometric coefficient of variation). Treatment was well tolerated without dose-limiting toxicity. The rate of complete or partial responses was 54.3%, and the overall mortality at 12-week follow-up was 28.3%. In first-line treatment of invasive aspergillosis, daily doses of up to 200 mg caspofungin were well tolerated and the maximum tolerated dose was not reached. Pharmacokinetics was linear. Response rates were similar to those previously reported for voriconazole and liposomal amphotericin.
authors.affiliation: 1st Department of Internal Medicine, University Hospital of Cologne, Kerpener Str 62, 50937 Cologne, Germany. oliver.cornely@ctuc.de
authors.forename: O A
authors.initials: OA
authors.lastname: Cornely
authors.forename: J J
authors.initials: JJ
authors.lastname: Vehreschild
authors.forename: M J G T
authors.initials: MJ
authors.lastname: Vehreschild
authors.forename: G
authors.initials: G
authors.lastname: Würthwein
authors.forename: D
authors.initials: D
authors.lastname: Arenz
authors.forename: S
authors.initials: S
authors.lastname: Schwartz
authors.forename: C P
authors.initials: CP
authors.lastname: Heussel
authors.forename: G
authors.initials: G
authors.lastname: Silling
authors.forename: M
authors.initials: M
authors.lastname: Mahne
authors.forename: J
authors.initials: J
authors.lastname: Franklin
authors.forename: U
authors.initials: U
authors.lastname: Harnischmacher
authors.forename: A
authors.initials: A
authors.lastname: Wilkens
authors.forename: F
authors.initials: F
authors.lastname: Farowski
authors.forename: M
authors.initials: M
authors.lastname: Karthaus
authors.forename: T
authors.initials: T
authors.lastname: Lehrnbecher
authors.forename: A J
authors.initials: AJ
authors.lastname: Ullmann
authors.forename: M
authors.initials: M
authors.lastname: Hallek
authors.forename: A H
authors.initials: AH
authors.lastname: Groll
mesh_terms: D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D000077336:Caspofungin; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D054714:Echinocandins / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D055666:Lipopeptides; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077336:Caspofungin