A new phase I study has concluded that the fixed-dose combination (FDC) of ambrisentan and tadalafil is bioequivalent to individual doses of the two drugs taken concurrently, offering potential benefits in terms of reduced costs and improved compliance for patients dealing with pulmonary arterial hypertension (PAH). This groundbreaking research promises to streamline treatment regimens and proves the viability of the FDC as an alternative therapeutic option.
Published in the June 2019 issue of Clinical Therapeutics, the study (DOI: 10.1016/j.clinthera.2019.04.007) conducted by a team led by Dr. Malek M. Okour from the Clinical Pharmacology Modeling and Simulation unit of GlaxoSmithKline, Upper Providence, PA, assessed the relative bioavailability and bioequivalence of four different FDC formulations of ambrisentan and tadalafil against the existing practice of co-administration of monotherapies.
Pulmonary arterial hypertension is a serious condition characterized by high blood pressure in the arteries that transport blood from the heart to the lungs. It can lead to shortness of breath, exercise intolerance, and heart failure. Both ambrisentan, a type of endothelin receptor antagonist, and tadalafil, a phosphodiesterase-5 inhibitor, have been individually approved for the treatment of PAH, and their combination has previously shown superior efficacy in preventing clinical failure events in this patient population compared to monotherapies.
The study (ClinicalTrials.gov identifier: NCT02688387) comprised three parts, engaging 174 screened participants, from which 112 were allocated into a randomized treatment sequence, and 100 completed the study with full adherence. Part one involved a crossover comparison of the relative bioavailability of four FDC formulations (10-mg ambrisentan + 40-mg tadalafil) against co-administered reference monotherapies. Subsequently, the second part tested granulation size effects on the selected FDC formulation’s relative bioavailability, while part three evaluated the bioequivalence of the chosen FDC at various dose strengths (10-mg/40-mg, 5-mg/20-mg, and 5-mg/40-mg), under fasted and fed conditions.
All FDC formulations tested were found to deliver pharmacokinetic parameters within the range of those seen with administration of the reference monotherapies, fulfilling the criteria for bioequivalence. Furthermore, the results indicated that granulation size had an insignificant impact on the bioavailability of the FDC, offering manufacturing flexibility. The adverse events during the study were mostly mild to moderate in severity, and no serious adverse reactions were reported, indicating an acceptable safety profile.
The success of the study could have far-reaching implications for the management of PAH. The development of a single pill combining two core medications simplifies the treatment process, potentially reducing the likelihood of medication errors and increasing patient adherence. The convenience of an FDC also helps address one of the challenges in managing chronic conditions – the burden of taking multiple medications with distinct dosing schedules.
This study’s findings propose that an ambrisentan/tadalafil FDC could replace co-administered monotherapies without compromising efficacy or safety. This could transform the therapeutic landscape for PAH by providing a simpler, more patient-friendly treatment regimen. The broader implications of this could lead to increased treatment adherence, resulting in improved patient outcomes and potentially reducing healthcare costs associated with the chronic management of PAH.
Keywords
1. Pulmonary Arterial Hypertension Treatment
2. Fixed-Dose Combination Therapy
3. Bioequivalence Study
4. Ambrisentan Tadalafil Combination
5. PAH Patient Compliance
References
1. Okour, M. M., Puri, A., Chen, G., Port, K., Berni, A., Khindri, S., … & Tenero, D. (2019). A Phase I Study to Show the Relative Bioavailability and Bioequivalence of Fixed-Dose Combinations of Ambrisentan and Tadalafil in Healthy Subjects. Clinical Therapeutics, 41(6), 1110–1127. https://doi.org/10.1016/j.clinthera.2019.04.007
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