Demonstrating Bioequivalence for a Lumacaftor Monosubstance Formulation Versus Orkambi® (Lumacaftor/Ivacaftor) in Healthy Subjects.

Background and objective: Lumacaftor is an active ingredient in the US Food and Drug Administration-approved combination medication Orkambi^®, which is used for treating cystic fibrosis. Experimental evidence suggests that lumacaftor can be used as a monotherapy to improve brain perfusion and memory in heart failure. To clinically assess this therapeutic intervention, a formulation with demonstrated bioequivalence to the currently approved combination product is required.

Methods: This comparative bioavailability and food-effect study compared lumacaftor pharmacokinetics in healthy patients following: (i) oral administration of lumacaftor (400 mg; Test Product) or Orkambi^® (lumacaftor 400 mg/ivacaftor 250 mg; Reference Product) in the fed state and (ii) oral administration of lumacaftor (400 mg; Test Product) in the fasted to fed state. Plasma lumacaftor concentrations were measured with a standard liquid chromatography with tandem mass spectrometry approach.

Results: The "Test-to-Reference ratio" of the geometric least-square means for maximum plasma concentration and area under the curve met the Food and Drug Administration-defined criteria for bioequivalence; median times to maximum plasma concentration values were not statistically different. The "Fed to Fasted ratio" of the geometric least-square means for maximum plasma concentration and area under the curve indicated a clear food effect on bioavailability. Lumacaftor exposure was approximately two times higher when administered with fatty foods than when taken in a fasting state. The monosubstance formulation was well tolerated.

Conclusions: We conclude that the lumacaftor monosubstance formulation delivers lumacaftor exposure that is not meaningfully different than the currently approved combination product.

Clinical trial registration: ClinicalTrials.gov identifier: NCT05968612.