Pharmacokinetics (PK) and Safety of Intravenous (IV) Brincidofovir (BCV) in Healthy Adult Subjects

Abstract Background BCV is a lipid conjugate nucleotide that has shown rapid viral clearance in patients with adenovirus infection and improved survival in animal models of smallpox. In preclinical studies in rats, IV BCV dosed twice weekly for up to 29 days was not associated with gastrointestinal (GI), hematopoietic, hepatic, or renal toxicity. This study evaluated the safety and PK of IV BCV in healthy subjects. Methods In this double-blind study, subjects were randomized 3:1 to receive IV BCV or placebo in sequential single ascending dose cohorts (Table 1). Plasma PK samples were collected over 7 days and assayed by HPLC-MS. Plasma BCV PK parameters were determined by non-compartmental analysis and dose proportionality was assessed. Safety assessments were collected over 14 days. Results Forty healthy male subjects (18–46 years, 83% White) were enrolled and completed the study. Plasma BCV Cmax and AUC∞ increased in proportion to dose (Table 1). AEs and alanine aminotransferase (ALT) elevations were dose- and infusion duration-related (Table 1). GI AEs were mild. All AEs and ALT elevations were transient and no serious AEs occurred. Table 1. IV BCV PK and Safety BCV 10 mg 2 h Infusion (n = 6) BCV 25 mg 2 h Infusion (n = 6) BCV 50 mg 2 h Infusion (n = 9) BCV 50 mg 4 h Infusion (n = 9) Pooled Placebo (n = 10) Plasma BCV PK Cmax (ng/mL) 613 (25%) 1412 (27%) 2952 (19%) 1586 (14%) NA AUC∞ (ng h/mL) 1312 (26%) 2889 (37%) 5948 (19%) 6570 (15%) NA Drug-related AEs Diarrhea 0 0 1 (11%) 3 (33%) 0 Nausea 0 0 0 2 (22%) 0 Decreased appetite 0 0 0 1 (11%) Headache 0 0 2 (22%) 2 (22%) 0 Pain, phlebitis at infusion site 0 0 1 (11%) 0 0 Elevated liver transaminasesa 0 0 0 1 (11%) 0 Cmax and AUC∞ presented as geometric mean (%CVb). aALT >2x ULN in 2 BCV 50 mg 4h infusion and 1 placebo subjects; 1 ALT elevation considered an AE. Conclusion Single doses of BCV 10–50 mg administered as a 2h IV infusion were well tolerated and not associated with significant clinical or laboratory abnormalities. BCV IV 10 mg and BCV IV 50 mg achieved geometric mean plasma BCV AUC∞ similar to and 4.5-fold, respectively, values achieved with BCV oral 100 mg tablets (Cmax = 251 ng/mL and AUC∞ = 1394 ng hours/mL). These data support evaluation of repeat dose administration in healthy subjects and virally-infected patients. Disclosures M. B. Wire, Chimerix: Employee and Shareholder, Salary. M. Morrison, Chimerix: Employee and Shareholder, Salary.M. Anderson, Chimerix: Employee and Shareholder, Sa