Population Pharmacokinetics of Escalating Doses of Caspofungin in a Phase II Study in Patients with Invasive Aspergillosis.
Antimicrob Agents Chemother. 2013 Jan 18;
Authors: Würthwein G, Cornely OA, Trame M, Vehreschild JJ, Vehreschild MJ, Farowski F, Müller C, Boos J, Hempel G, Hallek M, Groll AH
Objectives. Caspofungin (CAS) is approved for second line management of proven or probable invasive aspergillosis at a dose of 50 mg once daily (QD). Preclinical and limited clinical data support the concept of dose-dependent antifungal efficacy of CAS with preservation of its favourable safety profile. Little is known, however, about the pharmacokinetics of higher doses of CAS in patients.Methods. In a formal multicentre phase II dose escalation study, CAS was administered as 2 h infusion at doses ranging from 70 to 200 mg QD. CAS PK 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, 100 mg: 8, 150 mg: 9, 200 mg: 20, total: 46 patients). Drug concentrations in plasma were measured by liquid chromatography tandem mass spectroscopy. Population pharmacokinetic analysis (PopPK) was performed using NONMEM 7 software. Model evaluation was performed using bootstrap analysis, prediction corrected visual predictive check (pcVPC) as well as standardized visual predictive check (SVPC).Results. The four investigated dose levels showed 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 %). None of the other examined covariates (dose level, gender, age, serum bilirubin, creatinine clearance) improved the model further. Bootstrap results showed robustness of the final PopPK model. pcVPC and SVPC showed its predictability and further confirmed linear PK of CAS in the dosage range of 70 to 200 mg QD. Based on the final model, simulated peak plasma levels at steady state ranged from 13.8 to 39.4 mg/L (31 %), trough levels from 4.2 to 12.0 mg/L (49 %), and area under the concentration-time curve from 170 to 487 mg*h/L (34 %) for the dosage range of 70 to 200 mg QD (geometric mean, geometric coefficient of variation).Conclusion. CAS showed linear PK across the investigated dosage range of 70 to 200 mg QD. Drug exposure in the present study population was comparable to those in other populations.
PMID: 23335740 [PubMed - as supplied by publisher]