Program

PO1-11-7

Pharmacokinetics and Safety of the Oral Prostaglandin F2alpha Receptor Antagonist OBE022: A First-In-Human Study in Healthy Post-Menopausal Women

[Speaker] Ulrike Lorch:1
[Co-author] Oliver Pohl:2, Line Marchand:2, Jean-Pierre Gotteland:2
1:Richmond Pharmacology, UK, 2:ObsEva SA, 1228 Plan-les-Ouates, Geneva, Switzerland

Introduction:
Preterm birth remains a significant risk for later disability. The inhibition of the prostaglandin F2alpha (PGF2alpha; or FP) receptor has significant advantages for a tocolytic. The pro-drug OBE022 and its parent metabolite OBE002 are novel FP receptor antagonists. OBE022 is orally active and is under development for treating preterm labour. OBE022 and/or OBE002 have been shown to delay delivery in animal models of preterm labour and have reduced the strength and duration of contractions induced by either PGF2alpha or oxytocin in human myometrial strips.
Methods:
We performed a prospective, first in human, Phase I, dose escalation, placebo-controlled, randomised trial at a clinical study site in the UK.
Placebo, single ascending doses (SAD) of 10, 30, 100, 300, 1000 or 1300 mg, or multiple ascending doses (MAD) over seven days of 100, 300 or 1000 mg per day were administered to post-menopausal women volunteers. The food interaction was additionally appraised.
Results:
Subjects tolerated OBE022 well at all single and multiple doses. No clinically relevant changes in safety parameters were shown and there were no serious adverse events.
Observations showed that pro-drug OBE022 was readily absorbed and rapidly converted into its equally active stable metabolite OBE002. The plasma level of OBE002 rose with increasing doses of OBE022 reaching exposure levels that are anticipated to be clinically relevant within an hour following administration. There was no clinically significant food interaction with peak exposures reduced to 80% and AUC staying bioequivalent.
The mean t½ of OBE002 ranged between 8 and 11 hours following administration of a single dose and between 22 to 29 hours after multiple doses.
Conclusions:
Single or repeated oral daily administration of OBE022 has a favourable pharmacokinetic profile and is safe when dosed at 1000 mg per day in multiple doses and up to 1300 mg per day in single doses. There is no clinically relevant interaction with food. The pharmacokinetic values and safety profile fulfil the requirements for advancement to further clinical testing of OBE022 as tocolytic in preterm labour patients.
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