Treatment of spontaneous preterm labour with retosiban: a phase II pilot dose-ranging study

Abstract

Aims: The aims of the present study were to investigate the maternal, fetal and neonatal safety and tolerability, pharmacodynamics and pharmacokinetics of intravenous (IV) retosiban in pregnant women with spontaneous preterm labour (PTL) between 34^0/7 and 35^6/7 weeks' gestation.

Methods: In parts A and B of a three-part, double-blind, placebo-controlled, multicentre study, women were randomized 3:1 (Part A) or 2:1 (Part B) to either 12-h IV retosiban followed by a single dose of oral placebo (R-P) or 12-h IV placebo followed by single-dose oral retosiban (P-R).

Results: A total of 29 women were randomized; 20 to R-P and nine to P-R. An integrated analysis found that adverse events were infrequent in mothers/newborns and consistent with events expected in the population under study or associated with confounding factors. Retosiban was rapidly absorbed after oral administration, with an observed half-life of 1.45 h. Efficacy analyses included 19 women. While not statistically significant, those receiving R-P more frequently achieved uterine quiescence in 6 h (R-P, 63%; 95% credible interval [CrI]: 38, 84; P-R, 43%; 95% CrI: 12, 78) and more achieved a reduction of ≥50% in uterine contractions in 6 h (R-P, 63%; 95% CrI: 38, 84; P-R, 29%; 95% CrI: 4, 64). The number of days to delivery was increased in women receiving R-P (median 26 days for R-P vs. 13 days for P-R).

Conclusions: Intravenous retosiban has a favourable safety and tolerability profile and might prolong pregnancies in women with PTL. The study provides the rationale and dosing strategy for further evaluation of the efficacy of retosiban in the treatment of PTL.

Keywords: bioavailability; pregnancy; randomized control trial.

Figure 1

Subject disposition. *Completed investigational product (IP), defined as having received at least 95% of the infusion. ^†Six subjects excluded owing to protocol violation. ^‡Four subjects excluded owing to protocol violation. PD, pharmacodynamics; P‐R, placebo infusion over 12 h followed by a single oral dose of retosiban 125 mg; R‐P, retosiban infusion over 12 h followed by a single oral placebo dose

Figure 2

Maternal and fetal heart rate and maternal blood pressure. (A) Maternal and fetal heart rate. The dotted vertical line represents the end of the 12‐h intravenous (IV) retosiban infusion or administration of the oral dose. (B) Maternal blood pressure. The dotted vertical line represents the end of the 12‐h IV infusion and administration of the oral dose. Error bars represent the 95% Confidence interval

Figure 3

Mean plasma retosiban concentration–time plot. The solid line is the mean predicted from the pharmacokinetic model, and the open circles are the observed concentration data from the 14 patients who received the 12‐h intravenous infusion of retosiban and were included in the pharmacokinetic analysis

Figure 4

Number of days to delivery following treatment initiation. Middle line is the median, outer edge of box is the 25^th and 75^th quantile and the whiskers represent the min and max values