Confirmation of the Cardiac Safety of PGF2α Receptor Antagonist OBE022 in a First-in-Human Study in Healthy Subjects, Using Intensive ECG Assessments

Abstract

OBE022, a new orally active prostaglandin F_2α receptor antagonist (OBE022) with myometrial selectivity is being developed to reduce uterine contractions during preterm labor. This first-in-human study evaluated the effect of OBE022 following multiple doses on the QT interval in 23 healthy postmenopausal women, using the effect of a meal on QTc to demonstrate assay sensitivity. We report the cardiac safety outcome performed during the multiple ascending part of this trial. OBE022 was administered after a standardized breakfast on day 1 and in the fasted state from day 3 to day 9 wth a standardized lunch 4 hours after administration. Concentration-effect modeling was used to assess the effect of prodrug OBE022 and parent OBE002 on QTc after a single dose (days 1 and 3) and multiple doses (day 9). The concentration-response analysis showed the absence of QTc prolongation at all doses tested. Two-sided 90% confidence intervals of the geometric mean C_max for estimated QTc effects of OBE022 and OBE002 of all dose groups were consistently below the threshold of regulatory concern. The sensitivity of this study to detect small changes in the QTc was confirmed by a significant shortening of the QTc on days 1, 3, and 9 after standardized meals. This study establishes that neither prodrug OBE022 nor parent OBE002 prolong the QTc interval. The observed food effect on the QT interval validated the assay on all assessment days. Both the change from predose, premeal and the change from premeal, postdose demonstrated the specificity of the method.

Keywords: FP-receptor pharmacology; OBE022; QTc; QTc prolongation; QTc shortening; food effect; obstetrics; safety pharmacology; tocolytic.

Figure 1

(A) Structural formula of OBE022. (B) Structural formula of OBE002. OBE022 is the valine ester of OBE002, to which it is hydrolyzed in vivo.

Figure 2

Scatterplots for models OBE022, model OBE002, and model molar sum. (A) Relationship between ΔQTcF and exposure to OBE022. As this parent substance was rapidly converted to OBE002 the concentration range for OBE022 is lower than that for OBE002 (B). Correspondingly, the range for the molar sum of OBE022 and OBE002 (C) is predominantly determined by the concentration of OBE002.

Figure 3

Drug concentration of the dose groups and ΔΔQTcF for each dose group, plotted against time. Each row represents 1 dose group, and each column represents 1 day. A peak in ΔΔQTcF would follow the peaks of the drug concentrations if the drug effect on QTcF were delayed. This effect should be uniform across dose groups and most pronounced in the highest dose group. This is not the case. *Top value of the concentration scale represents 3 ng/mL for OBE022 and 1000 ng/mL for OBE002.

Figure 4

Consort diagram.

Figure 5

Arithmetic means and SEs of plasma concentrations of OBE022 and OBE002 at 3 different doses, on days 1 (single dose, fed), 3 (single dose, fasted), and 9 (steady state, fasted). The red line indicates a 1000‐mg dose, the green line a 300‐mg dose, and the blue line a 100‐mg dose.