BackgroundST-246® is an antiviral, orally bioavailable small molecule in clinical development for treatment of orthopoxvirus infections. An intravenous (IV) formulation may be required for some hospitalized patients who are unable to take oral medication. An IV formulation has been evaluated in three species previously used in evaluation of both efficacy and toxicology of the oral formulation.Methodology/Principal FindingsThe pharmacokinetics of ST-246 after IV infusions in mice, rabbits and nonhuman primates (NHP) were compared to those obtained after oral administration. Ten minute IV infusions of ST-246 at doses of 3, 10, 30, and 75 mg/kg in mice produced peak plasma concentrations ranging from 16.9 to 238 µg/mL. Elimination appeared predominately first-order and exposure dose-proportional up to 30 mg/kg. Short IV infusions (5 to 15 minutes) in rabbits resulted in rapid distribution followed by slower elimination. Intravenous infusions in NHP were conducted at doses of 1 to 30 mg/kg. The length of single infusions in NHP ranged from 4 to 6 hours. The pharmacokinetics and tolerability for the two highest doses were evaluated when administered as two equivalent 4 hour infusions initiated 12 hours apart. Terminal elimination half-lives in all species for oral and IV infusions were similar. Dose-limiting central nervous system effects were identified in all three species and appeared related to high Cmax plasma concentrations. These effects were eliminated using slower IV infusions.Conclusions/SignificancePharmacokinetic profiles after IV infusion compared to those observed after oral administration demonstrated the necessity of longer IV infusions to (1) mimic the plasma exposure observed after oral administration and (2) avoid Cmax associated toxicity. Shorter infusions at higher doses in NHP resulted in decreased clearance, suggesting saturated distribution or elimination. Elimination half-lives in all species were similar between oral and IV administration. The administration of ST-246 was well tolerated as a slow IV infusion.

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ABSTRACT. Nares Strait is one of three main passages of the Canadian Archipelago that channel relatively fresh seawater from the Arctic Ocean through Baffin Bay to the Labrador Sea. Oxygen isotopic profiles along the growth axis of bivalve shells, collected live over the 5 -30 m depth range from the Greenland and Ellesmere Island sides of the strait, were used to reconstruct changes in the hydrography of the region over the past century. The variability in oxygen isotope ratios is mainly attributed to variations in salinity and suggests that the northern end of Nares Strait has been experiencing an increase in freshwater runoff since the mid 1980s. The recent changes are most pronounced at the northern end of the strait and diminish toward the south, a pattern consistent with proximity to the apparently freshening Arctic Ocean source in the north and mixing with Baffin Bay waters as the water progresses southward. This increasing freshwater signal may reflect changes in circulation and ice formation that favor an increased flow of relatively fresh waters from the Arctic Ocean into Nares Strait.