ORAL OXYTOCIN ANTAGONIST PHARMACODYNAMICS IN PREGNANT/NONPREGNANT RHESUS MONKEY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Oxytocin antagonists could help delay preterm labor, which occurs in up to 12% of all human pregnancies and contributes to a variety of neonatal health problems. Current tocolytic agents for the pharmacological inhibition of uterine contractions have side-effects and limited efficacy. The orally active AS606521 is administered in a non-invasive manner, has a slow clearance, and is specific for the oxytocin receptor. However, pregnant animals, with increased blood volume and altered circulation, may have a different clearance compared to non-pregnant animals. The direct testing of drug efficacy in reducing uterine activity in primates during pregnancy, as well as placental transfer of the drug into amniotic fluid and fetal blood, are important aspects for future use in women. The similarity of rhesus and human pregnancy allows this study to have potential direct benefits to human medicine. A pharmacokinetic and pharmacodynamic study on the orally-active oxytocin antagonist AS606521 in a nonpregnant and pregnant rhesus monkey model was initiated. The goals are to compare the pharmacokinetics of AS606521 in pregnant and non-pregnant primates, to establish the effective plasma concentration ranges for blocking oxytocin-induced uterine contractions in pregnant rhesus monkeys and to confirm the reversibility of the inhibition by higher concentrations of oxytocin (rescue therapy).