Coadministration of the prostaglandin F2α receptor antagonist preterm labour drug candidate OBE022 with magnesium sulfate, atosiban, nifedipine and betamethasone.

Abstract

To investigate presence or absence of clinically relevant drug interactions (pharmacokinetic and safety/tolerability) of OBE022 with standard-of-care medicines for preterm labour, enabling coadministration and further clinical development. Part A: open-label, randomized, 3-period crossover assessing coadministration of single doses of OBE022 (1100mg) and MgSO4 . Part B: open-label, single-sequence crossover assessing the interactions following administration of OBE022 (1000mg/day) at steady state coadministered with single doses of atosiban, nifedipine and betamethasone. Twenty-five healthy nonpregnant women of reproductive age were enrolled (Part A: n=12; Part B: n=13). OBE022, alone or in combination with standard-of-care medications, was well tolerated. Headache and dizziness were the most frequently reported adverse events; dizziness occurred more often with the nifedipine/OBE022 combination. There were no clinically significant pharmacokinetic interactions when coadministered with MgSO4 . Co-administration had no notable effect on atosiban exposure. Atosiban reduced exposure to OBE002 (peak concentration [Cmax ] 22%, area under the concentration-time curve [AUC] 19%). Coadministration with betamethasone slightly increased betamethasone exposure (Cmax +18%, AUC +27%) and OBE002 exposure (Cmax +35%, AUC +15%). These changes were not considered clinically significant. Coadministration with nifedipine slightly increased OBE002 exposure (Cmax +29%, AUC +24%) and markedly increased nifedipine exposure (Cmax by 2-fold and AUC by 2-fold), which may be clinically significant. The use of OBE022, a PGF2α antagonist prodrug, in combination with standard-of-care medicines may provide new treatment alternatives for preterm labour. All tested combinations were well tolerated. Nifedipine doses could potentially be reduced or staggered when coadministered with OBE022.