Barusiban suppresses oxytocin-induced preterm labour in non-human primates.
BACKGROUND
Preterm labour (PTL) is a major cause of neonatal mortality and morbidity, and oxytocin (OT) antagonists are potential tocolytics. Atosiban (TRACTOCILE) is a mixed vasopressin V1A/OT antagonist registered for acute treatment of PTL in Europe. Other off-label drugs have serious side effects. Barusiban is a selective OT antagonist which has reached clinical development. A monkey model with OT-induced PTL was developed to compare barusiban and atosiban. In addition, the feasibility for long-term treatment of PTL with barusiban was explored.


METHODS
Conscious pregnant cynomolgus monkeys were monitored for intrauterine pressure (IUP). A sensor for IUP was implanted into the amniotic cavity, and biopotential sensors for electromyogram were attached to the uterus. For short-term experiments, individual low-dose OT infusions induced stable submaximal uterine contractions. Barusiban and atosiban were administered either as intravenous bolus or infusion at high or low doses. For long-term treatment, low-dose OT was infused daily for 3-6 hours to mimic PTL. In addition, continuous high-dose infusions of barusiban (150 microg kg-1 h-1) or fenoterol (3 microg kg-1 h-1) were administered.


RESULTS
Contractions of 15-40 mmHg were induced with individual OT infusions at 5-90 mU kg-1 h-1, and no OT-related desensitization occurred. Correlation was demonstrated between electromyograms and IUP curves. Barusiban was well tolerated and its potency was 4 times higher than atosiban's. Barusiban and atosiban demonstrated >95% efficacy. However, barusiban's duration of action was >13 hours (atosiban's 1-3 hours) and reversible with high-dose OT in emergency situations. OT control and fenoterol-treated monkeys delivered preterm (ca. day 154) and showed an increase in overall IUP. Barusiban-treated animals delivered normally following end of treatment (ca. day 163).


CONCLUSIONS
The presented telemetry model provides an excellent method to evaluate PTL drug candidates. OT induced stable repetitive contractions and no desensitisation. Barusiban and atosiban demonstrated high efficacy and rapid onset of action. Barusiban, a selective OT antagonist has higher potency and prolonged duration of action than atosiban. Barusiban effectively suppressed IUP during daily OT-challenges, delayed labour, and prolonged monkeys' pregnancy till term.
Reinheimer
Torsten M
TM
Non-Clinical Development, International PharmaScience Center, Ferring Pharmaceuticals A/S, Copenhagen S, Denmark. trr@ferring.com
D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006727:Hormone Antagonists / Q000008:administration & dosage* / Q000494:pharmacology; D008252:Macaca fascicularis; D009215:Myometrium / Q000187:drug effects; D007752:Obstetric Labor, Premature / Q000188:drug therapy* / Q000517:prevention & control; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D011247:Pregnancy; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors; D013686:Telemetry; D015149:Tocolytic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D014590:Uterine Contraction / Q000187:drug effects; D014668:Vasotocin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
D006727:Hormone Antagonists; D009842:Oligopeptides; D018045:Receptors, Oxytocin; D015149:Tocolytic Agents; C047046:atosiban; C517339:barusiban; D014668:Vasotocin