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Barusiban, A New Highly Potent and Long-Acting Oxytocin Antagonist: Pharmacokinetic and Pharmacodynamic Comparison with Atosiban in a Cynomolgus Monkey Model of Preterm Labor

Department of Non-Clinical Development (T.M.R.), Ferring Pharmaceuticals A/S, 2300 Copenhagen S, Denmark; Sierra Division (W.H.B., J.C.R., J.K.M., G.J.C.), Charles River Discovery and Development Services, Sparks, Nevada 89431; and Oregon National Primate Research Center (G.J.H.), Beaverton, Oregon 97006

Address all correspondence and requests for reprints to: Dr. Gary J. Chellman, Department of Toxicology, Charles River Laboratories, Preclinical Services, 587 Dunn Circle, Sparks, Nevada 89431. E-mail: gchellman{at}sbi.criver.com.

Preterm labor (PTL) represents a significant unmet clinical need that affects up to 20% of all pregnancies and is a leading cause of preterm delivery and associated neonatal morbidity and mortality. Therapeutic options are limited, with existing drug therapy (tocolytics) compromised by side effects and limited efficacy. Because oxytocin (OT) is likely to be involved causally in PTL, this study compared two OT receptor antagonists, barusiban and atosiban, for their tocolytic effects. OT was given to instrumented pregnant cynomolgus monkeys to induce contractions and simulate PTL. Barusiban or atosiban was then given iv (bolus or infusion) to evaluate inhibitory effects on uterine contractions, measured by telemetric recording of intrauterine pressure. Both antagonists had high efficacy (96–98% inhibition of intrauterine pressure) and rapid onset of action (0.5–1.5 h). Barusiban was three to four times more potent than atosiban, which was attributed to its higher affinity and selectivity for the OT receptor. Barusiban also had a much longer duration of action (>13–15 h, compared with 1–3 h for atosiban). The inhibitory effects of barusiban were reversible within 1.5–2.5 h by high-dose OT infusion. Overall, barusiban’s improved potency, long duration of action, and reversibility may provide an improved tocolytic for treatment of PTL.

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