Director of Clinical Pharmacology Bellus Health Inc Laval, Quebec, Canada
Background: BLU-5937 is a selective and non-competitive P2X3 antagonist in development for the treatment of Refractory Chronic Cough. In-vitro studies with BLU-5937 (at concentrations up to 400 µM) to assess interactions with target enzymes and transporters were conducted. BLU-5937 was identified as a weak CYP3A4 inducer (EC50=60 µM), BCRP inhibitor (IC50 =5.6 µM) and a weak inhibitor of P-gp (IC50 =30 µM) and OATP1B1 (IC50 =27 µM). Methods: Clinical relevance of these findings was explored in an open-label sequential Drug-Drug Interaction clinical study in 28 healthy subjects. The impact of repeated doses (200 mg BID) of BLU-5937 on the pharmacokinetics of single doses of substrates of CYP3A4 (midazolam, 5 mg), OATP1B1 (pravastatin, 40 mg), and BCRP (sulfasalazine, 500 mg) was investigated. Results: BLU-5937 did not impact midazolam exposure with LSM ratios ratio and 90% CI for AUC and Cmax within 80-125%. A weak interaction was observed with pravastatin, with LSM ratio of 140% for AUC. No clinically significant interaction was observed between BLU-5937 and sulfasalazine (LSM ratio of 116 and 117% for AUC and Cmax). A physiological based pharmacokinetic model was developed to predict the effect of BLU-5937 on P-gp substrates. Simulations using the Ki for P-gp inhibition showed no significant interactions with digoxin and dabigatran at anticipated therapeutic doses (25 mg or 50 mg BID). Using a 15-x reduced P-gp Ki, a minor increase in Cmax and no significant increase in AUC was predicted for digoxin and 56% and 44% increase in Cmax and AUC was predicted for dabigatran at the 50 mg BID dose of BLU-5937. A clinical study to validate results in dabigatran is planned. Conclusion: Data indicate that BLU-5937 is unlikely to perpetrate clinically meaningful DDIs at therapeutically relevant doses.
