Eugène Cox (1), Henrik Agerso (2), Thomas Senderovitz(2).
(1)Pharsight Corporation, Mountain View, USA; (2) Ferring Pharmaceuticals A/S, Copenhagen, Denmark.
Objectives: The objective of this study was to quantify the relationship between drug exposure and the inhibitory effect of the oxytocin antagonist atosiban on uterine contraction rate in women with pre-term labour.
Methods: Atosiban was administered to women with preterm labor at different dose levels as a single dose subcutaneous injection in a randomized, double-blind, placebo controlled, parallel study manner. The Uterine Contraction Rate (UCR) were recorded at 1-hour intervals up to 12 hours after drug administration using a tocodynamometer. Serial venous blood samples were collected and assayed for atosiban concentrations in order to determine the pharmacokinetic profile of atosiban. Uterine contractions rates were then related to plasma concentrations in order to quantify the in vivo pharmacodynamic profile of atosiban.
Results: Pharmacokinetic data were analyzed for each individual patient on the basis of a one-compartment pharmacokinetic model with first order absorption from the injection site. The mean (± SEM) values of clearance, volume of distribution and absorption rate for atosiban were 32± 0.2 L/hr, 46 ± 0.1 L and 7.5 ± 0.2/hr, respectively. A profound hysteresis was observed in the relationship between atosiban plasma concentrations and UCR and this hysteresis was accounted for using an effect compartmental model. The actual observed UCR was then related to the effect site concentration using a population pharmacodynamic model for count data assuming a Poisson distribution of the observed UCR. The estimate of the concentration that results in 50% of the maximal atosiban-induced reduction of UCR (EC50) was. 37± 2 ng/ml. The interpatient variability of the mean UCR value was estimated to be 8%. Also, a profound placebo response was observed during the time course of the study. Apart form standard diagnostic procedures, the model was further validated on the basis of a posterior predictive check.
Conclusion: The results of this study show that the in vivo pharmacodynamic action of atosiban can be adequately quantified on the basis of a population PK/PD model for UCR in patients with preterm labor.
Reference: PAGE 12 (2003) Abstr 459 [www.page-meeting.org/?abstract=459]
Poster: poster