Single-dose, Multiple-dose, and Population Pharmacokinetics of SUN13837 Injection, a Basic Fibroblast Growth Factor Mimic in Healthy Subjects

Authors: Shah B, Darling IM, Ludwig EA, Zahir H, Duchin K
Conference: ACCP
Keywords: neurology, PK, spinal cord injury, sun13837
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Abstract

SUN13837, a novel small molecule in development for the treatment of acute spinal cord injury and stroke with biological activities similar to basic fibroblast growth factor (bFGF) promotes cellular differentiation including angiogenesis and axonal outgrowth and provides neuronal protection without stimulating cell proliferation.

A first-in-human, randomized, double-blind, placebo-controlled study was conducted to assess safety, tolerability, and pharmacokinetics (PK) of SUN13837 in healthy subjects (escalating single intravenous [IV] dose of SUN13837: 0.04 to 1.92 mg/kg; 8 dose groups; 6 active and 2 placebo per dose group; 64 subjects). In a multiple-dose study, a daily IV dose of SUN13837 was administered for 7 days (0.25, 0.50, 1.00, and 1.50 mg/kg; 6 active and 2 placebo per group; 32 subjects). Interim population PK models were developed with pooled data from these Phase 1 studies and one additional Phase 1 PK study of SUN13837, administered 1 mg/kg intravenously to 28 healthy subjects. SUN13837 was safe and well tolerated. In general, Cmax and AUC for SUN13837 increased in a dose-proportional manner. Mean t1/2 values after single doses ranged between 12.0-17.9 hours. With multiple doses, steady state appears to be achieved by Day 5 and accumulation was minimal (20% based on AUC). Urinary recovery of SUN13837 ranged from 31.7%-60.9% after multiple doses. SUN13837 metabolites in plasma were identified. Three metabolites were measured with a validated LC/MS method after single and multiple doses. Three-compartment base structural PK models with linear elimination best described the SUN13837 and metabolite ASB15490 data. SUN13837 estimated clearance (15.5 L/h) and total volume of distribution (112.5 L) were similar to ranges obtained previously using noncompartmental analysis methods. Age was the most significant covariate; SUN13837 exposure increased modestly with advancing age. SUN13837 showed linear PK and minimal accumulation with once-daily regimen. Initial population PK models provide a starting basis for dose selection and optimization in the target population.

American College of Clinical Pharmacology (ACCP) Annual Meeting, September 27-29, 2015, San Francisco, CA

By B Shah, PhD, Inger Darling, PhD, Elizabeth A. Ludwig, PhD, H Zahir, PhD, K Duchin, PhD