WB-PBPK Model Analysis

The WB-PBPK model for caspofungin was constructed according to the scheme of 14 tissue compartments of the disposition model. Simulations were based on caspofungin physicochemical and the vitro data (Table 2). Tissue distribution was predicted using established tissue composition equations. Hepatic and renal caspofungin clearances were calculated by the PKplus model, as described in the method section. The results are shown in Table 3.
The observed and WB-PBPK model simulated mean plasma concentration-time profiles of caspofungin in healthy adults after intravenous doses of 20 mg, 40 mg, 70 mg and 100 mg are graphically presented in Figure 1. The predicted and observed pharmacokinetic parameters with the prediction accuracy are summarized
Simulated peak levels appear to be underestimated by 20% for all doses levels, but they were within the range of the observed SD. As shown in Figure 2, the predicted concentration-time-curve was in accordance with the observed mean values of healthy subjects with the multiple doses administration of 15 mg, 35 mg, 70/50 mg and 70 mg, which is the same to general patients with the dosage regimens of 70 mg, 100 mg, 150 mg and 200 mg (Figure 3). The GOF plot showed a good accuracy between predicted and observed data (Figure 5a-b). Only the simulated peak levels seemed to be underestimated in Gastroplus. For ICU patients with Child Pugh B, ICU patients on CRRT and HI patients, when using the WB-PBPK distribution model to simulate plasma concentrations, a reasonable match to the measured concentration range was observed (Figure 4). The GOF plot showed a good accuracy between predicted and observed data (Figure 5c-d). The simulated peak levels seemed to be underestimated by 10%, which were within the range of the observed SD. The simulated trough levels seemed to be overestimated by 5% in ICU patients, for HI patients, it showed a sufficient accuracy between predicted and observed data. The CL, Vss, t1/2, AUC, Cmax of different patients with different dosage regimens are shown in Table 3. The fold-error of all
Particularly, the PK parameters of ICU patients were recorded. At steady state, the AUC of the three multiple dosage regimens (70/35 mg, 70 mg q.d, 100 mg q.d) of caspofungin in ICU patients were 74.5 mg·h/L, 155.5 mg·h/L, 218.4 mg·h/L, respectively. The Cmax were 6.5 mg/L, 11.5 mg/L, 16.9 mg/L, respectively. After simulation of the reduction dose of 50/25 mg and dose escalating of 70 mg q.d, 100 mg q.d of moderate HI patients, we got the PK parameters of these patients. The AUC of these patients were 92.6 mg·h/L, 178.6 mg·h/L, 280 mg·h/L, respectively. The Cmax were 5.8 mg/L, 10.9 mg/L and 15.3mg/L, respectively. The results of all patients are shown in Table 3.
Figure 6a, 6b and 6c showed the relationship between Cmax, Cmin, AUC, CL and BW with the recommended dosage regimens of caspofungin in general patients (70/50 mg), ICU patients (70/50 mg) and moderate HI patients (70/35 mg). From these figures, we find that Cmin were constant in all investigated virtual patients and did not correlate to body weight or other covariates. This was also valided for the CL. But Cmax and AUC began a slow decline with the increase of body weight. The variation tendency was not obvious in HI