Atosiban

Atosiban (INN) is a synthetic peptide ([Mpa¹,D-Tyr(Et)², Thr⁴,Orn⁸]-oxytocin) which is a competitive antagonist of human oxytocin at receptor level.

In rats and guinea pigs, atosiban was shown to bind to oxytocin receptors, to decrease the frequency of contractions and the tone of the uterine musculature, resulting in a suppression of uterine contractions. Atosiban was also shown to bind to the vasopressin receptor, thus inhibiting the effect of vasopressin. In animals atosiban did not exhibit cardiovascular effects.

In human pre-term labour, atosiban at the recommended dosage antagonises uterine contractions and induces uterine quiescence. The onset of uterus relaxation following atosiban is rapid, uterine contractions being significantly reduced within 10 minutes to achieve stable uterine quiescence (≤4 contractions/hour) for 12 hours.

In healthy non-pregnant subjects receiving atosiban infusions (10 to 300 micrograms/min over 12 hours), the steady state plasma concentrations increased proportionally to the dose.

The clearance, volume of distribution and half-life were found to be independent of the dose.

In women in pre-term labour receiving atosiban by infusion (300 micrograms/min for 6 to 12 hours), steady state plasma concentrations were reached within one hour following the start of the infusion (mean 442 ± 73 ng/ml, range 298 to 533 ng/ml).

Following completion of the infusion, plasma concentration rapidly declined with an initial (t_α) and terminal (t_β) half-life of 0.21 ± 0.01 and 1.7 ± 0.3 hours, respectively. Mean value for clearance was 41.8 ± 8.2 litres/h. Mean value of volume of distribution was 18.3 ± 6.8 litres.

Plasma protein binding of atosiban is 46 to 48% in pregnant women. It is not known whether the free fraction in the maternal and fetal compartments differs substantially. Atosiban does not partition into red blood cells.

Atosiban passes the placenta. Following an infusion of 300 micrograms/min in healthy pregnant women at term, the fetal/maternal atosiban concentration ratio was 0.12. Two metabolites were identified in the plasma and urine from human subjects. The ratios of the main metabolite M1 (des-(Orn⁸, Gly-NH₂⁹)-[Mpa¹, D-Tyr(Et)², Thr⁴]-oxytocin) to atosiban concentrations in plasma were 1.4 and 2.8 at the second hour and at the end of the infusion respectively. It is not known whether M1 accumulates in tissues. Atosiban is found in only small quantities in urine, its urinary concentration is about 50 times lower than that of M1. The proportion of atosiban eliminated in faeces is not known. The main metabolite M1 is approximately 10 times less potent than atosiban in inhibiting oxytocin-induced uterine contractions in vitro. Metabolite M1 is excreted in milk.

There is no experience with atosiban treatment in patients with impaired function of the liver or kidneys. Renal impairment is not likely to warrant a dose adjustment, since only a small extent of atosiban is excreted in the urine. In patients with impaired hepatic function, atosiban should be used with caution.

It is unlikely that atosiban inhibits hepatic cytochrome P450 isoforms in humans.

No systemic toxic effects were observed during the two-week intravenous toxicity studies (in rats and dogs) at doses which are approximately 10 times higher than the human therapeutic dose, and during the three-months toxicity studies in rats and dogs (up to 20 mg/kg/day s.c.). The highest atosiban subcutaneous dose not producing any adverse effects was approximately two times the therapeutic human dose.

No studies were performed that covered fertility and early embryonic development. Reproduction toxicity studies, with dosing from implantation up to late stage pregnancy, showed no effects on mothers and fetuses. The exposure of the rat fetus was approximately four times that received by the human fetus during intravenous infusions in women. Animal studies have shown inhibition of lactation as expected from the inhibition of action of oxytocin.

Atosiban was neither oncogenic nor mutagenic in in vitro and in vivo tests.