Pharmacokinetic-Pharmacodynamic Target Attainment Analysis to Support VL-2397 Dose Selection for a Phase 2 Trial in Patients with Invasive Aspergillosis

BACKGROUND: VL-2397 is a novel antifungal agent in clinical development for treatment of invasive aspergillosis (IA). The analysis objectives were to: 1) develop a population PK model using data from a Phase 1 trial in healthy adult volunteers, 2) define the PK-PD driver of efficacy in a mouse model of IA, and 3) conduct PK-PD target attainment analyses to aid in Phase 2 dose selection for patients with IA. METHODS: Data from two studies were used: a dose fractionation study in a mouse model of IA and a Phase 1 study in healthy adult volunteers receiving single- and multiple-ascending doses of intravenous (IV) VL-2397 ranging from 3 mg to 1200 mg daily. Mouse lung fungal burden (LFB) measured on Day 4 after infection with Aspergillus fumigatus FP1305 (MIC of 1 µg/mL) was used to assess the predictive value of three measures of VL-2397 exposure: total-drug AUC(0-24):MIC (tAUC(0-24):MIC), total-drug C(max):MIC, and total-drug %T>MIC; total drug was used because serum protein binding is similar in mice and humans. A population PK model for VL-2397 in humans was developed in NONMEM v7.1.2 and formed the basis of Monte Carlo simulations. The model was also fit to mouse PK data to estimate the VL-2397 exposure in mice. RESULTS: VL-2397 concentration-time data in humans revealed nonlinear PK behavior consistent with highly-bound compounds. A robust fit to the data was obtained using a two-compartment model with linear elimination and concentration-dependent binding in both central and peripheral compartments. The results of the dose fractionation study suggested that tAUC(0-24):MIC was the most predictive (r(2) = 0.713) driver of efficacy, with a value of 21.8 on Day 1 associated with a 2-log reduction in LFB on Day 4. Comparisons of the simulated VL-2397 tAUC(0-24):MIC on Day 1 in humans receiving daily dosing regimens of 300 mg, 600 mg, and 900 mg of VL-2397 to the 2-log target (figure) suggested that a dose of 600 mg Q24 would provide robust (99.9%) PK-PD target attainment up to an A. fumigatus MIC of 2 µg/mL. CONCLUSION: The PK-PD driver of efficacy for VL-2397 was tAUC(0-24):MIC and a value of 21.8 was associated with a 2-log reduction in LFB in a mouse model of IA. PK-PD target attainment assessments indicate that a VL-2397 dose of 600 mg IV Q24 will provide adequate target attainment up to an MIC of 2 µg/mL. DISCLOSURES: C. M. Rubino, Vical Incorporated: Consultant, Consulting fee; L. R. Smith, Vical Incorporated: Employee, Salary and Stock Options; M. P. Mammen, Vical Incorporated: Employee, Salary and Stock Options; A. M. Hopkins, Vical Incorporated: Employee, Salary and Stock Options; E. A. Lakota, Vical Incorporated: Consultant, Consulting fee; S. M. Sullivan, Vical Incorporated: Employee, Salary and Stock Options