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

Single-Dose Safety and Pharmacokinetics of ST-246, a Novel Orthopoxvirus Egress Inhibitor▿

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 ST-246 was generally well tolerated with no serious adverse events, and no subject was withdrawn from the study due to ST-246.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

Plasma pharmacokinetic estimates for BALB/c mice, New Zealand white Hra: (NZW) SPF albino rabbits, beagle dogs and cynomolgus monkeys following repeat oral dosing of ST-246 by gavage for 7 consecutive days in New Zealand white Hra: (NZW) SPF albino rabbits and beagle dogs and 28 consecutive days in BALB/c mice and cynomolgus monkeys.

<p>Extraction ratio = Cl/F/Cardiac Output.</p

Observed versus scaled human plasma pharmacokinetics, recommended and given FIH dose levels for ST-246.

<p>Extraction ratio = Cl/F/Cardiac Output.</p><p>¶ = First-in human (FIH) dose calculated by a slight modification (no safety factor applied) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061514#pone.0061514-Mahmood4" target="_blank">[26]</a> of the pharmacologically guided approach provided in the United State Food and Drug Administration (USDFA) draft guidance <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061514#pone.0061514-US1" target="_blank">[27]</a> and expressed as follows:</p><p>Dose (mg) = Animal AUC (h_*µg/mL) × scaled human Cl/F (L/h).</p><p>Where the applied AUC is the lowest observed systemic exposure value among the animal species utilized in this evaluation.</p><p>a = Plasma clearance scaled by simple allometry.</p><p>b = Plasma clearance scaled by MLP-corrected allometry.</p><p>c = Apparent volume of distribution scaled by simple allometry.</p><p>d = t_1/2 calculated from the simple allometry human plasma clearance (Cl/F) and simple allometry human apparent volume of distribution (V_D/F) using the equation: t1_/2 = In2*(V_D/F)_scaled/(Cl/F)_scaled.</p><p>e = t_1/2 calculated from the MLP-corrected allometry human plasma clearance (Cl/F) and simple allometry human apparent volume of distribution (V_D/F) using the equation: t_1/2 = In2*(V_D/F)_scaled/(Cl/F)_scaled.</p><p>f = Extraction ratio calculated from simple allometry human plasma clearance (Cl/F).</p><p>g = Extraction ratio calculated from the MLP-corrected allometry human plasma clearance (Cl/F).</p><p>h = Human pharmacokinetic estimates from a double-blind, randomized, placebo-controlled study following single daily oral administrations of ST-246 (in capsule form) at a dose of 400 mg for 14 days in non-fasted healthy adult human volunteers.</p><p>i = Human pharmacokinetic estimates from a double-blind, randomized, placebo-controlled study following single daily oral administrations of ST-246 (in capsule form) at a dose of 600 mg for 14 days in non-fasted healthy adult human volunteers.</p><p>j = Human pharmacokinetic estimates from a double-blind, randomized, placebo-controlled study following single daily oral administrations of ST-246 (in capsule form) at a dose of 800 mg for 21 days in non-fasted healthy adult human volunteers.</p

Allometric coefficient, allometric exponent and coefficient of determination values from linear regression analysis of pharmacokinetic parameters from BALB/c mice, New Zealand white Hra: (NZW) SPF albino rabbits, cynomolgus monkeys and beagle dogs following repeat oral administration of ST-246 by gavage for 7 consecutive days in New Zealand white Hra: (NZW) SPF albino rabbits and beagle dogs and 28 consecutive days in BALB/c mice and cynomolgus monkeys.

<p>♀ & φ = Values from simple allometry.</p><p>Φ = Values from MLP-corrected allometry.</p

Plasma pharmacokinetic estimates for BALB/c mice, New Zealand white Hra: (NZW) SPF albino rabbits, beagle dogs and cynomolgus monkeys following repeat oral dosing of ST-246 by gavage for 7 consecutive days in New Zealand white Hra: (NZW) SPF albino rabbits and beagle dogs and 28 consecutive days in BALB/c mice and cynomolgus monkeys.

<p>Plasma pharmacokinetic estimates for BALB/c mice, New Zealand white Hra: (NZW) SPF albino rabbits, beagle dogs and cynomolgus monkeys following repeat oral dosing of ST-246 by gavage for 7 consecutive days in New Zealand white Hra: (NZW) SPF albino rabbits and beagle dogs and 28 consecutive days in BALB/c mice and cynomolgus monkeys.</p

Plots of mean plasma concentration versus time profiles in cynomolgus monkeys following repeat oral administrations of ST-246 by gavage at a dose of 100 mg/kg for 28 consecutive days.

<p>The adjacent plot represents the corresponding semi-logarithmic plot.</p

Molecular structure of ST-246.

<p>Molecular structure of ST-246.</p

Linear regression analysis of log- transformed apparent volume of distribution for BALB/c mice, New Zealand white Hra: (NZW) SPF albino rabbits, cynomolgus monkeys and beagle dogs versus log-transformed corresponding animal body weight, following oral (gavage) administration of ST-246 by gavage at a dose of 2000, 100, 100 and 30 mg/kg, respectively.

<p>Linear regression analysis of log- transformed apparent volume of distribution for BALB/c mice, New Zealand white Hra: (NZW) SPF albino rabbits, cynomolgus monkeys and beagle dogs versus log-transformed corresponding animal body weight, following oral (gavage) administration of ST-246 by gavage at a dose of 2000, 100, 100 and 30 mg/kg, respectively.</p

Plots of mean plasma concentration versus time profiles in beagle dogs, following repeat oral administrations of ST-246 by gavage at a dose of 30 mg/kg seven consecutive days.

<p>The adjacent plot represents the corresponding semi-logarithmic plot.</p