Phase II Dose Escalation Study of Caspofungin for Invasive Aspergillosis

1st Department of Internal Medicine, University Hospital of Cologne, Kerpener Str 62, 50937 Cologne, Germany.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 09/2011; 55(12):5798-803. DOI: 10.1128/AAC.05134-11
Source: PubMed


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.

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Available from: Jörg Janne Vehreschild, Feb 13, 2014
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    • "Echinocandin monotherapy might be an alternative , as the in vitro activity of echinocandins against A . fumigatus appear unaffected by the presence of an azole resistance mechanism ( van Ingen et al . , 2015 ) . Caspofungin has been shown to be efficacious for patients with IA ( Viscoli et al . , 2009 ; Herbrecht et al . , 2010 ; Cornely et al . , 2011 ) , but the success rates were disappointing with outcomes of 50% or less . One experimental study has shown comparable effec - tiveness of L - AmB against IA due to wild - type and azole - resistant Aspergillus , indicating that azole resistance does not diminish the efficacy of L - AmB ( Seyedmousavi et al . , 2013c ) . Thus , for azo"
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