Population Pharmacokinetic Modeling of VL-2397, A Novel Systemic Antifungal Agent: Analysis of a Single and Multiple Ascending Dose Study in Healthy Subjects.

Population Pharmacokinetic Modeling of VL-2397, A Novel Systemic Antifungal Agent: Analysis of a Single and Multiple Ascending Dose Study in Healthy Subjects.

Antimicrob Agents Chemother. 2019 Apr 15;:

Authors: Kovanda LL, Sullivan SM, Smith LR, Desai AV, Bonate PL, Hope WW

Abstract
VL-2397, a novel, systemic antifungal agent, has potent in vitro and in vivo fungicidal activity against Aspergillus species. Plasma concentrations from a Phase 1 study were used to construct a population pharmacokinetic (PPK) model for VL-2397.Methods: Healthy subjects aged 18 to 55 years received single doses of VL-2397 ranging from 3 to 1200mg, multiple daily doses of 300, 600, or 1200mg for 7 days, or 300mg three-times/day for 7 days followed by 600mg daily for 21 days. Plasma samples were collected throughout the dosing intervals.Results: Sixty-six subjects provided 1,908 concentrations. Drug concentrations over time increased less than dose proportional for doses above 30mg. Dose-normalized concentrations plotted over time did not overlap. A 3-compartment non-linear saturable binding model fit the data well. Clearance increased with dose, mean values ranged from 0.4 L/h at 3mg and 8.5 L/h at 1200mg. Mean volume in the central compartment ranged from 4.8 to 6.9 L across doses. In the first 24 hours, once daily dosing results in a rapid decrease in concentrations by hour 16 to approximately 1 mg/L, regardless of dose, with slow clearance over time. Administration of 300mg every 8 hours achieved concentrations above 1 mg/L over an entire 24-hour period. There was a significant relationship of body surface area to clearance.The data suggests that VL-2397 has non-linear saturable binding kinetics. Protein binding is the likely primary source of the non-linearity. The PPK model can now be used to optimize dosing by bridging the kinetics to efficacious pharmacodynamic targets.

PMID: 30988142 [PubMed – as supplied by publisher]

Source: Industry