G. Würthwein(1), O.A. Cornely(2,3), J. J. Vehreschild(3), M.J.G.T. Vehreschild(3), F. Farowski(3), M. Hallek (3), A.H. Groll(4)
(1)Centre for clinical trials, ZKS Münster (BMBF 01KN1105), University Hospital Münster, Münster, Germany, (2)Clinical Trials Center Cologne, ZKS Köln (BMBF 01KN1106), University of Cologne, Cologne, Germany, (3)Department I of Internal Medicine, University of Cologne, Cologne, Germany, (4) Infectious Disease Research Program, Department of Pediatric Hematology/Oncology, University Children's Hospital, Muenster, Germany
Objectives: Caspofungin (CAS) is used for management of proven or probable invasive fungal infections. In a multicenter phase II dose escalation study, dose-dependent pharmacokinetics of CAS was studied.
Methods: CAS was administered as 2h infusion at doses from 70 to 200 mg QD. CAS pharmacokinetic sampling (n=468 samples) was performed on day 1 and at peak and trough time points at days 4, 7, 14, and 28 (70 mg: 9 (96), 100 mg: 8 (80), 50 mg: 9 (94), 200 mg: 20 (198) patients (plasma samples)). Trough levels were analysed descriptively. Population pharmacokinetic analysis was performed using NONMEM and Pirana. For model evaluation, Bootstrap analysis, prediction corrected (pcVPC) as well as standardized (SVPC) visual predictive check were performed.
Results: There was no difference in log-transformed dose-normalised trough levels of CAS (ANOVA). CAS concentration data fitted best to a two-compartment model with proportional error model, interindividual variability (IIV) on clearance (CL), central (V1) and peripheral (V2) volume of distribution, covariance on CL and V1, interoccasion variability (IOV) on CL and body weight as covariate on CL and V1 (CL 0.411 L/h ± 29 %, IOV on CL: 16 %, V1: 5.785 L ± 29 %, Q: 0.843 L/h, V2: 6.53 L ± 67 %). No one of the other covariates (dose level, sex, body weight, age, serum bilirubin, creatinine clearance) further improved the model. Bootstrap results show robustness of the final PopPK model, VPC and SVPC confirm its predictability. Based on the final model, simulated peak plasma concentrations at steady state ranged from 13.8 to 39.4 mg/L (31 %), trough concentrations from 4.2 to 12.0 mg/L (49 %), and area under the concentration-time curve from 170 to 487 mg/L*h (34 %) for the dosage range of 70 to 200 mg QD (geometric mean, geometric coefficient of variation).
Conclusion: CAS showed linear pharmacokinetics across the investigated dosage range of 70 to 200 mg QD. Following administration of 100 mg QD, drug exposure in the study patients were slightly higher (7 %) relative to results found in healthy volunteers.
Reference: PAGE 21 (2012) Abstr 2360 [www.page-meeting.org/?abstract=2360]
Poster: Oncology