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Purpose: We developed a PPK model for CPT, the active form of prodrug CPT fosamil, in Phase 2/3 patients with cSSSI or CAP given intravenous (IV) or intramuscular (IM) CPT fosamil.
Methods: Data from 185 Phase 1 subjects and 92 cSSSI patients were pooled to develop a PPK model. Data from 128 CAP patients were used for external validation. Phase 1 subjects received CPT fosamil 50-2000 mg IV over 1 h q12h or q24h for up to 14 days, or IM injection for up to 5 days. Patients with cSSSI or CAP received CPT fosamil 600 mg over 1 h q12h and PK samples were collected and analyzed. Covariates were assessed using stepwise forward selection (α=0.01) and backward elimination (α=0.001). Monte Carlo simulation and bootstrap analyses were used for model evaluation.
Results: A 3-compartment (CMT) model with zero-order input or dual-phase first-order IM absorption and first-order elimination described the prodrug. A 2-CMT model with rapid first-order conversion of prodrug to CPT and parallel linear (CLlin=3.06 L/h) and saturable elimination (CLi=11.6 L/h; km=9.62 mg/L) described CPT with good agreement between observed and population (r2=0.927) and individual (r2=0.983) predictions. CLi and Vc were higher in patients than in Phase 1 subjects. Creatinine clearance (CrCL) was the major determinant of CPT exposure; both CLi and CLlin increased with CrCL. Simulated patients with 30<CrCL<50 mL/min/1.73 m2 given 400 mg and those with CrCL≤30 mL/min/1.73 m2 given 300 mg had comparable AUC0-12 relative to those with normal renal function given 600 mg IV q12h. The 90% prediction intervals captured observed CPT data in both cSSSI and CAP patients.
Conclusion: A PPK model was developed to describe the time-course of CPT in plasma and identify relevant PK covariate effects. This model evaluated adjustments for renal insufficiency and assessed pharmacokinetic-pharmacodynamic relationships in patients treated with CPT fosamil.