1971. Use of PK/PD Systems Analyses to Determine the Optimal Fixed Dosing Regimen of Iclaprim (ICL) for Phase III ABSSSI Clinical Trial
Session: Poster Abstract Session: Antimicrobial Pharmacokinetics and Pharmacodynamics
Saturday, October 29, 2016
Room: Poster Hall
Posters
  • 1971_IDWPOSTER.pdf (332.7 kB)
  • 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 AUC0-24hss, AUC/MIC, and T > MIC while adverse events may be linked to Cmaxss. 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 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.

    David Huang, MD, PhD, Motif BioSciences, New York, NY and Thomas Lodise, PharmD, PhD, Albany College of Pharmacy, Albany, NY

    Disclosures:

    D. Huang, Motif BioSciences: Employee , Salary

    T. Lodise, None

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