LAUSR

Abstract Background APX001 is a novel antifungal agent which is rapidly converted to the active metabolite APX001A. APX001A exhibits in vitro activity against many clinically important yeast and fungi, including echinocandin- and azole-resistant Candida species. Given this activity, intravenous (IV) and oral (PO) formulations of APX001 are being developed for the treatment of patients with candidemia or invasive candidiasis. Phase 1 data were used to develop a population PK (PPK) model to describe the time-course of APX001A in plasma. Methods The PPK model was developed using 3,736 plasma PK samples collected from 128 healthy subjects who received APX001 single and multiple IV and PO doses ranging from 10 to 1,000 mg. Instantaneous conversion was assumed by scaling input doses by the molecular weight ratio of APX001A to APX001. After development of the structural PK model, stepwise forward and backward selection procedures were used to identify significant covariate relationships. Model qualification included standard goodness-of-fit metrics and prediction-corrected visual predictive check (PC-VPC) plots. Results A two-compartment model with zero-order IV input, or first-order PO absorption with lag time to account for the apparent delay in oral absorption, best described APX001A plasma PK. Exponential error models were used to estimate interindividual variability (IIV) for all parameters. Interoccasion variability was estimated for the absorption rate constant, bioavailability, and lag time. Body weight was identified as a statistically significant predictor of the IIV on the volume of the central and peripheral compartments. The PPK model provided an accurate and unbiased fit to the plasma data based on individual- and population-predicted concentrations (r2 = 0.977 and 0.873, respectively). The PC-VPC plots for the final PPK model (Figure 1) demonstrated good alignment between observed concentrations and the model predicted 5th, 50th, and 95th percentiles. Conclusion A PPK model describing APX001A plasma PK following IV or PO doses was successfully developed. This model will be useful for generating simulated APX001A exposures for use in pharmacokinetic–pharmacodynamic target attainment analyses to support APX001 dose selection. Disclosures M. Trang, Amplyx Pharmaceuticals, Inc.: Research Contractor, Research support. J. C. Bader, Amplyx Pharmaceuticals, Inc.: Research Contractor, Research support. E. A. Ople, Amplyx Pharmaceuticals, Inc.: Employee, Salary. W. G. Kramer, Amplyx Pharmaceuticals, Inc.: Scientific Advisor, Consulting fee. M. R. Hodges, Amplyx Pharmaceuticals, Inc.: Employee, Salary. S. M. Bhavnani, Amplyx Pharmaceuticals, Inc.: Research Contractor, Research support. C. M. Rubino, Amplyx Pharmaceuticals, Inc.: Research Contractor, Research support.