Comparison of the safety and pharmacokinetics of ST-246® after i.v. infusion or oral administration in mice, rabbits and monkeys

Abstract

Background: ST-246® is an antiviral, orally bioavailable small molecule in clinical development for treatment of orthopoxvirus infections. An intravenous (i.v.) formulation may be required for some hospitalized patients who are unable to take oral medication. An i.v. formulation has been evaluated in three species previously used in evaluation of both efficacy and toxicology of the oral formulation.

Methodology/principal findings: The pharmacokinetics of ST-246 after i.v. infusions in mice, rabbits and nonhuman primates (NHP) were compared to those obtained after oral administration. Ten minute i.v. 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 i.v. 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 i.v. infusions were similar. Dose-limiting central nervous system effects were identified in all three species and appeared related to high C(max) plasma concentrations. These effects were eliminated using slower i.v. infusions.

Conclusions/significance: Pharmacokinetic profiles after i.v. infusion compared to those observed after oral administration demonstrated the necessity of longer i.v. infusions to (1) mimic the plasma exposure observed after oral administration and (2) avoid C(max) 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 i.v. administration. The administration of ST-246 was well tolerated as a slow i.v. infusion.

Conflict of interest statement

Competing Interests: Yali Chen, Adams Amantana, Shanthakumar R. Tyavanagimatt, Daniela Zima , X. Steven Yan, Gopi Kasi, Morgan Weeks, Melialani A. Stone, William C. Weimers, Peter Samuel, Ying Tan, Kevin F. Jones, Daniel R. Lee, Shirley S. Kickner, Kady M. Honeychurch, Robert Jordan, Dennis E. Hruby and Janet M. Leeds are employees of SIGA Technologies. Bradley M. Saville, Martin Lauzon and Alan McIntyre are employees of Charles River Laboratories. ST-246 is patented (US Patent No. for ST-246 is 7,737,168 issued on June 15, 2010) and currently being evaluated in clinical development. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Figure 1. Plasma concentration time curves for oral and IV administration of ST-246 in mice.

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.

Figure 2. Plasma concentrations over time after IV and oral administration in New Zealand White Rabbits.

Plasma concentrations of ST-246 over time are shown after oral administration of 100 mg/kg (purple squares); bolus IV administration of 1 mg/kg (red circles); or a 5- minute IV slow push of 3 (blue triangles), 30 (black triangles), or 60 mg/kg (green diamonds). A 15-minute IV infusion of 3 mg/kg (blue hexagons) is also shown. Each curve is the mean with standard deviations from two male and two female rabbits.

Figure 3. ST-246 plasma concentrations over time after oral or 4 hours IV infusions in cynomolgus monkeys.

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.

Figure 4. Exposure after different dosing regimens of either 20 or 30 mg/kg ST-246 to cynomolgus monkeys.

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).