Enhanced Oral Bioavailability of Mecitentan via Self-Microemulsifying Drug Delivery System: Pharmacokinetic Assessment in Animal Model

Background: The modern treatment of pulmonary arterial hypertension is focused on such a drug as Mecitentan, a dual endothelin receptor antagonist. The low water solubility coupled with a strong first-pass hepatic clearance of this compound leads to poor orally bioavailability, which limits usefulness as treatment. The elimination of these limitations is necessary to obtain fair systematic drug exposure and maximise clinical efficacy. Objective: This study was aimed at determining the pharmacokinetic effectiveness of Mecitentan administered through self- micro emulsifying drug delivery system (SMEDDs) and comparing the observation with that of a plain drug in preclinical animal model. Method: In male Wistar rats, oral administration of Mecitentan-loaded SMEDDS (10 mg/kg), time to maximum concentration, maximal concentration, area under the curve, and extent of distribution of the drug were observed and compared to those observed upon administration of plain Mecitentan. Blood samples were taken in pre-determined intervals during the span of 24 h and level of plasma in Mecitentan was quantified through a validated HPLC method. The non-compartmental analysis performed in Phoenix WinNonlin 81 determined the pharmacokinetic parameters namely Cmax, Tmax, AUC0→t, AUC0→∞, t 1/2, and MRT. Results: Comparative estimates of SMEDDs and a conventional suspension indicated that SMEDDs provided a significant increase in oral bioavailability. In particular, SMEDDs did yield a 38 % increased Cmax (721.43 vs. 523.43 ng /ml) and a 308 % greater AUC0→∞ ( 11841.99 vs. 2902.95 ng·h /ml) (p < 0.001). At the same time, there was an increased elimination half-life of SMEDDs (1.99-6.44 h), and Tmax was accelerated, which testifies to faster absorption. Conclusion: SMEDDS formulation improved Mecitentan's pharmacokinetics, improving absorption and systemic exposure. These nonclinical studies demonstrate that SMEDDS can overcome solubility-related biopharmaceutical limitations and improve Mecitentan's therapeutical profile for pulmonary arterial hypertension. DOI: https://doi.org/10.52783/jchr.v15.i4.9055