ECCMID4 Apr 2019 15:14
O1162 Pharmacokinetics of iclaprim by age, weight, race and renal/hepatic function in patients with acute bacterial skin and skin structure infections: phase III REVIVE trials
Stephanie Noviello*1, Lynda Berne, Jack Beusmans, William Knebel
1 Motif BioSciences, New York, United States
Background: Nearly 40% of patients hospitalized for ABSSSI are elderly (= 65 years of age). In the Phase 3 studies, REVIVE-1 and REVIVE-2, population pharmacokinetics (PPK) of iclaprim, a diaminopyrimidine dihydrofolate reductase inhibitor, was evaluated by age in patients with ABSSSI.
Materials/methods: Iclaprim plasma concentrations were obtained from 589 patients treated with iclaprim 80 mg fixed dose infused over 2 hours every 12 hours for 5-14 days. Samples were drawn pre-infusion and 5-15 minutes, 1-3h, and 5-7h post-infusion on Day 1, at 48 to 72 hours after initiating study treatment, and at the end-of-treatment visit. Data were analyzed using PPK analysis. Baseline covariates included age, weight, gender, race, Child-Pugh score, and eGFR.
Results: This full 2-compartment PPK model indicated that 589 iclaprim-treated patients had a median (range) area under the curve (AUC) of 5924h•ng/mL (744, 10979h•ng/mL), median maximum serum concentration (Cmax) of 651ng/mL (148, 2715ng/mL), and clearance of 26.7L/h. Median (min-max) age of these patients was 49 years (18-92 years) with 14% =65 years old; weight ranged from 41-162kg; 64% were male; demographics were similar between the arms. Iclaprim clearance (CL) was primarily affected by age; CL decreased by about 10% for each decade above 50 years. There was no effect of weight, gender, renal function, hepatic function, or race on CL. The size of the effect of age on AUC was small with a high correlation (R2=0.957); the AUC was predicted to be approximately 1.2-fold greater in patients =65 years old than the AUC in patients <65 years old. Cmax increased by approximately 10% in patients =65 years old. These modest changes in AUC and Cmax were not considered clinically meaningful.
Conclusions: In the Phase 3 REVIVE studies, clearance was not impacted by weight, gender, race, renal function or hepatic function. The AUC and Cmax levels in patients =65 years old were slightly higher than in younger adults, likely due to slower CL. These differences were not clinically significant and dose adjustment of iclaprim in elderly patients is not warranted. In addition, no iclaprim dose adjustments are needed for obese or renally impaired patients.
29TH ECCMID
13-16 APRIL 2019 AMSTERDAM, NETHERLANDS
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