Interaction study of atosiban withlabetalol or betamethasone

Pharmacokinetic interactionstudies of atosiban with labetalol or betamethasone in healthy female volunteers

B Buur Rasmussen, L Seiding Larsen, T Senderovitz. BJOG International Journal of Obstetrics and Gynaecology 112 pp 1-8 2005; Article in Press.

This paper is presenting the results of two open-label interaction studies with concomitant administration of either labetalol or betamethasone to determine any possibility of a clinically relevant interaction between the compounds.

Methods: This study was conducted as two separate trials.

Study 1: Open-label, single-dose atosiban, multiple-dose labetalol, interaction study.

N =14 healthy female volunteers.

Day 1: 12 hour i.v. infusion of 114.75 mg atosiban

Day 2-4: Labetalol 100 mg p.o. twice daily

Day 5: Combined treatment

Study 2: Open-label, single-dose, randomized, three-way crossover interaction study.

N = 18 healthy female volunteers.

3 separate treatments of:

  • 12 hour i.v. infusion of 114.75mg atosiban
  • Single i.m. injection of 12 mg betamethasone
  • The two compounds in combination

The washout period between administrations was 7 days.

Results:

Study 1: Treatment with atosiban alone or in combination with labetalol resulted in similar mean concentration-time curves. Labetalol had no clinically relevant influence on the bioavailability of atosiban. For labetalol, the co-administration with atosiban did not affect the extent of bioavailability (AUCss) of labetalol but Cmax decreased by 36% and tmax increased by 45 min. The administration of atosiban and labetalol in combination resulted in similar tolerability profile to that of each substance administered alone.

Study 2: Betamethasone in combination with atosiban led to similar mean plasma concentration-time curves as with each drug alone. Pharmacokinetic parameters did not differ markedly between treatments. The tolerance was similar for the co-administration as with each substance alone.

The co-administration of atosiban with labetalol or betamethasone had no clinically relevant influence on their bioavailability or tolerability.

Study 1:

In preterm birth the prevalence of pregnancy-induced hypertension is approximately 10%. Labetalol is one of the most frequently prescribed antihypertensives in pregnant women. Therefore due to the frequent co-administration of labetalol with atosiban it was found necessary to assess the risk of a possible pharmacokinetic interaction between the two compounds.

Study 2:

It is estimated that the corticosteroids, betamethasone or dexamethasone, are administered in almost all women in PTL in order to increase fetal lung maturation. In a clinical setting, atosiban and betamethasone will often be used concomitantly, as atosiban will delay preterm delivery and leave enough time for betamethasone to become effective. Due to this fact is was decided to conduct an interaction study between atosiban and betamethasone.

Based on the findings from the 2 above cited interaction studiesit can be concluded that neither co-administration of atosiban with labetalol or betamethasone will have any drug-drug interactions that could result in pharmacokinetic implications with regards to bioavailability or tolerability of the test compounds.

  • Atosiban is the licensed, evidence-based tocolytic of choice offering proven safety and efficacy for mother and baby, as documented in large, well-designed, randomised controlled trials1-3
  1. Romero R, Sibai BM, Sanchez-Ramos L, et al. An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind, placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol 2000; 182: 1173–1183.
  2. Valenzuela G, Sanchez-Ramos L, Romero R, et al. Maintenance treatment of preterm labor with the oxytocin antagonist atosiban. Am J Obstet Gynecol 2000; 182: 1184–1190.
  3. The Worldwide Atosiban versus Beta-agonists Study Group. Effectiveness and safety of the oxytocin antagonist atosiban versus beta-adrenergic agonists in the treatment of preterm labour. The Worldwide Atosiban versus Beta-agonists Study Group. Brit J Obstet Gynaecol 2001; 108: 133–142.

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