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

Abstract

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.

Barusiban suppresses oxytocin-induced preterm labour in non-human primates

“…During short-term treatment a total eight monkeys were included, and each group consisted of three (or two) pregnant females [16]. The groups participated in up to four phases of treatment that were separated by a 24–48 h washout period.…”

Atosiban versus fenoterol as a uterine relaxant for external cephalic version: randomised controlled trial

“…The mean time for both drugs to reach their maximum concentrations in serum is 30 minutes, with a half life of 1.4 hours for atosiban and 2 hours for fenoterol. [13][14][15][16][17] A limitation of our study is that the doctors and the women could not be blinded to treatment owing to the obvious and common side effects of beta mimetics. However, side effects were never a reason for stopping the intervention, and bias due to non-blinding was virtually absent.…”

“…18 The success rate in our study corresponds to that in other cohort studies and randomised controlled trials comparing tocolytic agents. [10][11][12][13][14][15][16][17][18][19][20] Our sample size calculation was still adequate to detect the anticipated increase in cephalic presentations at 30 minutes after ECV, as lower or higher baseline rates have more statistical power to detect similar changes of 10% absolute risk difference.…”

The Effect of Oxytocin and an Oxytocin Antagonist on the Human Myometrial Proteome

“…All samples (n ¼ 5) were taken prior to the onset of labor (gestation range 37-39 weeks, median 38 weeks) from the upper incisional edge of the lower uterine segment before oxytocic administration. Biopsies (1 cm  1 cm  1 cm) were immediately placed in Krebs solution (NaCl 118, NaHCO 3 …”