Abstract
Iclaprim is a bacterial dihydrofolate reductase inhibitor that is currently being evaluated in two phase 3 trials for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI). Prior animal infection model studies suggest that the pharmacokinetic/pharmacodynamic (PK/PD) drivers for efficacy are area under the concentration-time curve from 0 to 24 h at steady state (AUC(0-24ss)), AUC/MIC, and time above the MIC during the dosing interval (T > MIC), while QTc prolongation was associated with the maximal concentration at steady state (C(maxss)) in a thorough QTc phase 1 study. Using PK data collected from 470 patients from the previously conducted phase 3 complicated skin and skin structure infection (cSSSI) trials, population PK modeling and Monte Carlo simulation (MCS) were used to identify a fixed iclaprim dosage regimen for the ongoing phase 3 ABSSSI studies that maximizes AUC(0-24ss), AUC/MIC, and T > MIC while minimizing the probability of a C(maxss) of ≥800 ng/ml relative to the values for the previously employed cSSSI regimen of 0.8 mg/kg of body weight infused intravenously over 0.5 h every 12 h. The MCS analyses indicated that administration of 80 mg as a 2-h infusion every 12 h provides 28%, 28%, and 32% increases in AUC(0-24ss), AUC/MIC, and T > MIC, respectively, compared to values for the 0.8-mg/kg cSSSI regimen, while decreasing the probability of a C(maxss) of ≥800 ng/ml, by 9%. Based on PK/PD analyses, 80 mg iclaprim administered over 2 h every 12 h was selected as the dosing scheme for subsequent phase 3 clinical trials.