Modeling and Simulation of Caspofungin in Icu Patients

R. Brüggemann1, L. Martial1, J. Schouten2, P. Pickkers1, H. van Leeuwen3, A. van Zanten4, D. de Lange5, P. Verweij1, E. Muilwijk1, T. P. C. Dorlo6;

Author address: 

1Radboud Univ. Nijmegen Med. Ctr., Nijmegen, Netherlands, 2Canisius Wilhelmina Hosp., Nijmegen, Netherlands, 3Rijnstate, Arnhem, Netherlands, 4Gelderse Vallei Hosp., Ede, Netherlands, 5Univ. Med. Ctr. Utrecht, Utrecht, Netherlands, 6Uppsala Univ., Uppsala, Sweden, Uppsala, Sweden

Abstract: 

Objectives: 

Caspofungin (CAS) is an echinocandin antifungal agent used for the treatment of invasive candidiasis. CAS is administered intravenous at a dose of 70mg on day 1, followed by 50mg QD. Maintenance dose should be 70mg for BW ≥80kg and 35mg for patients with Child-Pugh B (CPB). AUC/MIC is used as PK-PD target parameter. CPB is used in patients with cirrhotic livers. Reducing CAS based on CPB in non-cirrhotic patients may result in suboptimal exposure. We aimed to confirm this using a population PK approach. 

Methods: 

CAS PK data from a study in ICU patients (21 patients; median(range) age and BW were 71(45-80) years and 75(50-99)kg; N=419 observations) were available. A POP-PK model was built (NONMEM 7.2, Pirana, PsN, R). The following dosing regimens were simulated (in a cohort of 1706 patients with median(range) BW 76(39-145) kg): licensed regimens (a) 70/50 for BW<80kg; 70/70 (for BW>80kg); (b)70/35 for CPB; adapted regimens (c) 100/70 only for BW≥80; (d)100/50 only for BW>80kg and CPB. Target attainment based on preclinical caspofungin PK target (AUC/MIC≥865) for C.albicans was assessed on day 14 for two relevant MICs (0.06 and 0.125). 

Results: 

A 2-compartment PK model best fitted the CAS data. BW was scaled linear on V1 and allometric on CL. IIV on all parameters was estimated and a full omega-block was used. CPB could not be confirmed as a covariate on any parameter. Median AUC(95%CI) were for (a) BW≤80kg 106(37-316), BW>80kg 116(39-348); (b) BW≤80kg 75(26-218) and BW>80kg 59(20-178); (c) 117(39-355); (d) 84(28-254). PK target attainment (MIC0.06) was for (a) BW≤80kg 87%, BW>80kg 90%; (b) BW≤80kg 71% and BW>80kg 57%; (c) 90% and (d) 77% (only BW>80kg). PK target attainment (MIC0.125) was for (a) BW≤80kg 50%, BW>80kg 56%; (b) BW≤80kg 30% and BW>80kg 18%; (c) 56% and (d) 35% (only BW>80kg). 

Conclusions: 

Based on MS a higher loading dose of 100 mg can be considered. CAS maintenance dose should not be reduced in non-cirrhotic patients based on CPB as it results in 16-38% lower target attainment, increasing the risk of therapy failure.

abstract No: 

A-022
    • ICAAC 55th (2015)