Pharmacokinetic interaction studies of atosiban with labetalol or betamethasone in healthy female volunteers.

OBJECTIVES

In two separate trials, we studied the concomitant administration of atosiban with labetalol and betamethasone to determine any possibility of a clinically relevant pharmacokinetic interaction.

DESIGN

Study 1 was an open-label, single dose atosiban, multiple dose labetalol, interaction study. Study 2 was an open-label, randomised, three-period crossover pharmacokinetic study.

SETTING

The studies were carried out at the Clinical Pharmacology Unit of AAI Deutschland GmbH & Co KG, Neu-Ulm, Germany.

POPULATION

The study population consisted of healthy female volunteers.

METHODS

In Study 1, 14 healthy female volunteers participated. On study day 1, a 12-hour intravenous infusion of 114.75 mg atosiban was administered; on days 2-4, participants received labetalol orally (100 mg twice daily), and on study day 5 they received the combined treatment. In Study 2, a total of 18 healthy female volunteers received, on three separate occasions, a 12-hour intravenous infusion of 114.75 mg atosiban, a single intramuscular injection of 12 mg betamethasone or the two drugs in combination.

MAIN OUTCOME MEASURE

For Study 1, the outcome parameter for atosiban was area under the plasma concentration-time curve (AUC); the study parameters for labetalol were AUC, maximum plasma concentration (C(max)) and time to C(max) (t(max)). In Study 2, AUC, C(max) and time to C(max) (t(max)) were assessed for atosiban and betamethasone.

RESULTS

Labetalol had no clinically relevant influence on the bioavailability (AUC) of atosiban. For labetalol, the co-administration with atosiban did not affect the extent of bioavailability, however, C(max) decreased by 36% and t(max) increased by 45 minutes. The C(min) was not affected by atosiban. The betamethasone and atosiban combination led to similar mean plasma concentration-time curves as the administration of each substance alone. Pharmacokinetic parameters (AUC, C(max), t(max)) did not differ markedly between treatments and all 90% CIs for ratios between treatments were fully within limits (80-125%). The co-administration of atosiban with labetalol or betamethasone resulted in similar tolerability to each substance alone.

CONCLUSION

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