1421. IV Brincidofovir (BCV): Pharmacokinetics (PK) and Safety of Multiple Ascending Doses (MAD) in Healthy Subjects

Background BCV is a lipid conjugated nucleotide analog that has shown rapid viral clearance with oral administration in patients with adenovirus infection, and improved survival in animal models of smallpox. Phase I single ascending dose evaluation of IV BCV demonstrated that 2 hour infusions of 10, 25, and 50 mg were well tolerated and not associated with significant adverse events (AEs) or laboratory abnormalities. This study evaluated the safety and PK of multiple ascending doses of IV BCV in healthy subjects. Methods Twenty-eight subjects were to be randomized 3:1 to receive blinded IV BCV or placebo in sequential MAD cohorts (Table A). Study drug was given twice a week (BIW) for 2 weeks or once a week (QW) for 4 weeks. Plasma PK samples were collected on Day 1 and after the last dose and assayed by HPLC-MS. Plasma BCV PK parameters were determined by noncompartmental analysis and dose proportionality and accumulation was assessed. Safety assessments were performed during the dosing period through 14 days post last dose. Results Twenty-seven male and female subjects (29–65 years, 93% White) were enrolled and 26 completed the study. Plasma BCV Cmax and AUC∞ increased in proportion to dose with no accumulation (Table A). AEs were generally mild and included diarrhea and headache. Alanine aminotransferase (ALT) elevations were asymptomatic and resolved upon cessation of dosing. No serious AEs occurred.Table A. BCV PK on Day 1 and Safety Plasma BCV PK1 BCV 10 mg BIW 2-hour Infusion (n = 9) BCV 20 mg QW 2-hour Infusion (n = 6) BCV 20 mg QW 1-hour Infusion (n = 5) Pooled Placebo (n = 7) C max (ng/mL) 553 (33%) 1,110 (19%) 1,720 (19%) NA AUC∞ (ng*h/mL) 1,374 (34%) 2,982 (23%) 2,919 (18%) NA Drug-related AEs in >2 subjects Diarrhea 0 3 (50%) 1 (20%) 0 Headache 4 (44%) 3 (50%) 3 (60%) 4 (57%) Fatigue 0 2 (33%) 0 2 (29%) 1. Cmax and AUC∞: geometric means (%CVb). Conclusion Multiple doses of IV BCV given as 10 mg BIW or 20 mg QW were generally safe and well tolerated. Mild diarrhea was reported only after IV BCV 20 mg QW. As seen with oral BCV, ALT increases were reversible upon cessation of drug, and were not associated with hyperbilirubinemia. BCV exposure was dose-proportional and no accumulation was observed. The data support evaluation of repeat dose administration in virally infected patients. Disclosures O. Naderer, Chimerix: Employee, Salary. V. Schuck, Chimerix: Research Contractor, Consulting fee. M. Morrison, Chimerix: Employee, Salary. M. Anderson, Chimerix: Employee, Salary. T. Arumugham, Chimerix: Employee, Salary. J. Dunn, Chimerix: Employee, Salary.