Use of PK/PD Systems Analyses to Determine the Optimal Fixed Dosing Regimen of Iclaprim (ICL) for Phase III ABSSSI Clinical Trial

Background: ICL is a novel dihydrofolate reductase inhibitor antibiotic that is currently in Phase 3 clinical development. Studies indicated that PK/PD drivers for efficacy are AUC_0-24hss, AUC/MIC, and T > MIC while adverse events may be linked to Cmax_ss. This analysis employed PK/PD modeling and simulation to estimate an optimal fixed dosing scheme for the Phase III ABSSSI trials designed to maximize both efficacy and safety.

Methods: Using PK data collected from 470 patients from the previously conducted Phase III ABSSSIs trials (ASSIST-1 & -2) population PK modeling and Monte Carlo simulation (MCS) were used to identify a fixed ICL dose regimen that maximized AUC_0-24hss, AUC/MIC, and T > MIC (efficacy parameters) while minimizing probability of a Cmax_ss ≥ 800 ng/mL (parameter that may be associated with adverse events) relative to 0.8 mg/kg IV, infused over 0.5 hours, Q12H (“base case” regimen used in ASSIST-1 & 2). For these analyses, the S. aureus MIC₉₀ of 120 ng/mL identified in worldwide surveillance studies from patients with SSSI and hospital acquired bacterial pneumonia was employed.

Results: Comparison of median (IQR) PK/PD metrics for the candidate fixed and based ICL dosing regimens are shown in Table. The MCS analyses indicate that administration of 80 mg as a 2 hr infusion Q12H will provide a 28%, 28%, 32%, increase in AUC_0-24hss, AUC/MIC, & T > MIC, respectively, compared to base case regimen while decreasing the probability of Cmax_ss ≥ 800 ng/mL by 9%.

	Iclaprim Dosing Regimens
Parameter	0.8 mg/kg/0.5 hr	64 mg/2hr	72 mg/2hr	80 mg/2hr
Cmaxss, ng/mL (IQR)	702 (572-953)	524 (411-679)	590 (462-764)	655 (514-849)
AUC0-24ss (IQR)	3865 (2992-5394)	3970 (3092-5540)	4466 (3479-6233)	4962 (3865-6926)
AUC/MIC, hr (IQR)	32 (24-45)	33 (26-46)	37 (29-52)	41 (32-58)
T > MIC, % (IQR)	39 (28-55)	45.0 (35-61)	48.3 (38-65)	51.7 (41-70)

Conclusion: Based on PK/PD system analyses, ICL 80 mg administered over 2 hr Q12H was selected as the dosing regimen for ABSSSI Phase III studies. This regimen conferred a greater likelihood of antibacterial efficacy while potentially improving the safety profile relative to the dosing regimen used in previous phase III trials.