Comparison of the Safety and Pharmacokinetics of ST-246® after IV Infusion or Oral Administration in Mice, Rabbits and Monkeys

ST-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. plasma concentrations. These effects were eliminated using slower IV infusions. 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

Comparison of pharmacokinetic parameters for ST-246 after oral administration and IV administration to New Zealand White rabbits.

<p>EOI, end of infusion.</p><p>IV, intravenous.</p><p>PO, per oral.</p

Comparison of pharmacokinetic parameters for ST-246 after oral administration to female BALB/c mice and 10-minute IV infusion in female CD-1 mice (parameters at each dose were calculated from concentrations from three individual mice at each time point, thus no statistical information is available).

<p>IV, intravenous.</p><p>PO, per oral.</p

Exposure after different dosing regimens of either 20 or 30 mg/kg ST-246 to cynomolgus monkeys.

<p>The mean and standard deviation values for the plasma concentrations over time are shown for different dosing regimens of (A) 20 mg/kg or (B) 30 mg/kg. The dosing regimens included oral administration (3 males and 3 females in each dose group, green diamonds), 4 hour IV infusion (2 males and 2 females in each dose group, red circles), 6 hour IV infusion (2 males and 2 females in each dose group, blue diamonds), and BID two 4 hour IV infusions initiated 12 hours apart (4 males and 4 females in each dose group, black diamonds).</p

Plasma concentration time curves for oral and IV administration of ST-246 in mice.

<p>The means and standard deviations of the plasma concentrations over time are shown after oral administration of ST-246 to female BALB/c mice at doses of 30 (chartreuse hexagons) and 1000 mg/kg (purple squares). The means and standard deviations of the plasma concentrations over time after 10 minute IV infusions to female CD-1 mice at 3 (red circles), 10 (blue triangles), 30 (black triangles), and 75 mg/kg (green diamonds). Each time point is the mean value from three individual mice.</p

ST-246 plasma concentrations over time after oral or 4 hours IV infusions in cynomolgus monkeys.

<p>Plasma concentration of ST-246 after a single oral dose of 3 (chartreuse hexagons), 10 (purple squares), or 30 mg/kg (white circles) compared to the plasma concentration time curves after 4 hour IV infusion of 1 (red circles), 3 (blue triangles), 10 (black triangles), or 30 mg/kg (green diamonds) in cynomolgus monkeys. Each curve shows the means and standard deviations. For oral administration there were 3 males and 3 females in each dose group while for the IV infusion there were 2 males and 2 females in each dose group.</p

Comparison of pharmacokinetic parameters for ST-246 after oral administration and IV infusions in cynomolgus monkeys.

<p>SOI, start of infusion.</p><p>IV, intravenous.</p><p>PO, per oral.</p><p>BID, twice a day.</p