Work

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

Year: 2016

Type: article

Abstract: Background. ICL is a novel dihydrofolate reductase inhibitor antibiotic that is currently in Phase III 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 and -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 hour 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%. Conclusion. Based on PK/PD system analyses, ICL 80 mg administered over 2 hours 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. Disclosures. D. Huang, Motif BioSciences: Employee, Salary

Source: Open Forum Infectious Diseases

DOI: 10.1093/ofid/ofw172.1519

Authors: David Huang, Thomas Lodise

Institutions: Motif BioSciences (United States), Albany College of Pharmacy and Health Sciences

Language: English

Topic: Antibiotics Pharmacokinetics and Efficacy

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,053