
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 AUC0-24hss, AUC/MIC, and T > MIC (efficacy parameters) while minimizing probability of a Cmaxss ≥ 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 AUC0-24hss, AUC/MIC, & T > MIC, respectively, compared to base case regimen while decreasing the probability of Cmaxss ≥ 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.

D. Huang,
Motif BioSciences:
Employee
,
Salary
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