Single-dose safety and pharmacokinetics of ST-246, a novel orthopoxvirus egress inhibitor

Abstract

ST-246 is a novel, potent orthopoxvirus egress inhibitor that is being developed to treat pathogenic orthopoxvirus infections of humans. This phase I, double-blind, randomized, placebo-controlled single ascending dose study (first time with humans) was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 in healthy human volunteers. ST-246 was administered in single oral doses of 500, 1,000, and 2,000 mg to fasting healthy volunteers and 1,000 mg to nonfasting healthy volunteers. ST-246 was generally well tolerated with no serious adverse events, and no subject was withdrawn from the study due to ST-246. The most commonly reported drug-related adverse event was neutropenia, which was found, upon further analysis, not to be treatment related. ST-246 was readily absorbed following oral administration with mean times to maximum concentration from 2 h to 3 h. Absorption was greater in nonfasting volunteers than in fasting volunteers. Administration of ST-246 resulted in exposure levels predicted to be sufficient for inhibiting orthopoxvirus replication compared to exposure levels in nonhuman primates in which ST-246 protected animals from lethal orthopoxvirus infection.

FIG. 1.

Mean plasma ST-246 concentration-time profiles following single-dose administration of ST-246. Symbols represent oral administration of ST-246 at 500 mg (diamonds), 1,000 mg (triangles), and 2,000 mg (squares) of ST-246 to fasting volunteers and 1,000 mg (circles) to nonfasting (fed) volunteers.

FIG. 2.

Pharmacokinetic values for oral administration of ST-246 in humans and nonhuman primates. The C_max values (A) and AUC_0-∞ values (B) for humans and nonhuman primates given ST-246 orally are shown. Doses of 500 mg (300 mg/m²), 1,000 mg (600 mg/m²), and 2,000 mg (1,200 mg/m²) of ST-246 were given to fasting human volunteers (red squares), a dose of 1,000 mg (600 mg/m²) was given to nonfasting (fed) human volunteers (yellow square), and 90 mg (360 mg/m²) was given to fasting (dark blue circles) or nonfasting (light blue circles) nonhuman primates. The means ± standard deviations (error bars) are shown. The 1,000-mg symbol representing the human nonfasting condition is slightly offset for clarity.