Use of Pharmacokinetic and Pharmacodynamic Analyses to Determine the Optimal Fixed Dosing Regimen of Iclaprim for Treatment of Serious Gram-Positive Infections [PublishAheadOfPrint]

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 models studies suggest that the pharmacokinetic and pharmacodynamics (PK/PD) drivers for efficacy are area under the curve from 0-24 hours at steady state (AUC_0-24hss), AUC/minimum inhibitory concentration (MIC), and time above the MIC during the dosing interval (T > MIC) while QTc prolongation was associated to 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 infection (cSSSI) trials, population PK modeling and Monte Carlo simulation were used to identify a fixed iclaprim dosage regimen for its ongoing Phase 3 ABSSSI studies that maximized AUC_0-24hss, AUC/MIC, and T > MIC while minimizing probability of a C_maxss ≥ 800 ng/mL relative to the cSSSI regimen of 0.8 mg/kg intravenously infused over 0.5 hours, every 12 hours. The MCS analyses indicated that administration of 80 mg as a two hour infusion every 12 hours provides a 28%, 28%, and 32% increase in AUC_0-24hss, AUC,/MIC, & T > MIC, respectively, compared to the 0.8 mg/kg cSSSI regimen, while decreasing the probability of C_maxss ≥ 800 ng/mL by 9%. Based on PK/PD analyses, iclaprim 80 mg administered over two hours every 12 hours was selected as the dosing scheme for its subsequent Phase 3 clinical trials.

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