Population pharmacokinetics of apramycin from first-in-human plasma and urine data to support prediction of efficacious dose

Abstract

Background: Apramycin is under development for human use as EBL-1003, a crystalline free base of apramycin, in face of increasing incidence of multidrug-resistant bacteria. Both toxicity and cross-resistance, commonly seen for other aminoglycosides, appear relatively low owing to its distinct chemical structure. Objectives: To perform a population pharmacokinetic (PPK) analysis and predict an efficacious dose based on data from a first-in-human Phase I trial. Methods: The drug was administered intravenously over 30min in five ascending-dose groups ranging from 0.3 to 30mg/kg. Plasma and urine samples were collected from 30 healthy volunteers. PPK model development was performed stepwise and the final model was used for PTA analysis. Results: A mammillary four-compartment PPK model, with linear elimination and a renal fractional excretion of 90%, described the data. Apramycin clearance was proportional to the absolute estimated glomerular filtration rate (eGFR). All fixed effect parameters were allometrically scaled to total body weight (TBW). Clearance and steady-state volume of distribution were estimated to 5.5L/h and 16L, respectively, for a typical individual with absolute eGFR of 124mL/min and TBW of 70kg. PTA analyses demonstrated that the anticipated efficacious dose (30mg/kg daily, 30min intravenous infusion) reaches a probability of 96.4% for a free AUC/MIC target of 40, given an MIC of 8mg/L, in a virtual Phase II patient population with an absolute eGFR extrapolated to 80mL/min. Conclusions: The results support further Phase II clinical trials with apramycin at an anticipated efficacious dose of 30mg/kg once daily.