The pharmacokinetic interaction of the selective PGF2α receptor antagonist OBE022 on co-administration with MgSO4, atosiban, nifedipine or betamethasone

[Speaker] Ulrike Lorch:1
[Co-author] Jorg Taubel:1,2, Oliver Pohl:3, Line Marchand:3, Jean-Pierre Gotteland:3
1:Richmond Pharmacology, St. George's University, UK, 2:St. George's University London, UK, 3:ObsEva SA, 1228 Plan-les-Ouates, Switzerland

Background: Preterm birth remains the major cause of perinatal mortality and morbidity. OBE022 is a novel, orally-active prostaglandin F2alpha; receptor antagonist under development for treatment of preterm labour. In clinical practice, tocolytics are co-administered with betamethasone for lung maturation and MgSO4 for neuroprotection. Tocolytic drugs of different modes of action may be used in combination to increase efficacy, without adversely affecting mother or foetus. This Phase 1 drug-drug interaction study aimed to investigate the effect of OBE022 on pharmacokinetic parameters, safety and tolerability when co-administered with betamethasone, magnesium sulfate (MgSO4) and currently used tocolytics (EudraCT: 2016-001958-18).
Methods: We performed an open-label, randomised, three-period crossover study assessing co-administration of OBE022 (1100 mg) and MgSO4 (15.5g) in 12 healthy premenopausal women. We also performed an open-label, single-sequence crossover study assessing the interactions of single doses of OBE022 (1000 mg/d) at steady-state co-administered with atosiban (60.75 mg), nifedipine (20 mg) and betamethasone (12 mg) in 12 healthy premenopausal women. We determined pharmacokinetic parameters and conducted standard safety assessments.
Results: There were no relevant mutual pharmacokinetic interactions between OBE022 and MgSO4. OBE022 had no effect on atosiban. However, atosiban slightly reduced exposure to OBE002, the pharmacologically active metabolite of the pro-drug OBE022 (Cmax -28%, AUC 21%). OBE022 co-administered with betamethasone slightly increased betamethasone exposure (Cmax +18%, AUC +27%) and that of OBE002 (Cmax +30%, AUC +15%). These changes were not considered clinically relevant. OBE022 co-administered with nifedipine slightly increased OBE002 exposure (Cmax +29%, AUC +24%) and markedly increased nifedipine exposure (Cmax +133%, AUC +137%). All drugs, alone or in combination, were well tolerated. Headache and dizziness were the most frequent adverse events reported with dizziness occurring more often with OBE022/nifedipine (seven subjects) than with nifedipine alone (two subjects) or OBE022 alone (one subject).
Conclusions: There were no clinically relevant pharmacokinetic interactions between OBE022 and MgSO4, betamethasone or atosiban, whereas nifedipine exposure doubled. Co-administration of OBE022 with MgSO4, betamethasone and tocolytic drugs provided no safety concerns and could be an effective strategy for preventing/delaying preterm delivery.
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