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.
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).
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).
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.
- ICAAC 55th (2015)