Pharmacokinetic Characterization and Comparative Bioavailability of an Innovative Orodispersible Fixed-Dose Combination of Ivermectin and Albendazole: A Single Dose, Open Label, Sequence Randomized, Crossover Clinical Trial in Healthy Volunteers

Abstract

Soil-transmitted helminths are intestinal worm diseases transmitted through the soil.Available treatments are albendazole and/or ivermectin. The co-administration ofexisting drugs is an appropriate strategy. A fixed-dose combination adds practicaladvantages mainly considering mass drug administration. The aim is to characterizepharmacokinetics and to evaluate the comparative bioavailability of an innovative fixeddosecombination of ivermectin/albendazole 18/400 mg compared with the marketedreferences. Seventy-eight healthy volunteers were included in this laboratory-blinded,randomized, three-treatment, three-period crossover study. Each subject received asingle dose of ivermectin/albendazole 18/400 mg (1 tablet); ivermectin 3mg (6 tablets);and albendazole 400 mg (1 tablet). Serial blood samples for the pharmacokinetic analysiswere obtained pre-dose and up to 72 h post-dose. Plasma concentrations of ivermectinH2B1a, ivermectin H2B1b, albendazole, and albendazole sulfoxide were analyzed by LCMS/MS. Pharmacokinetic parameters were estimated by a non-compartmental analysisand bioavailability compared through a bioequivalence analysis. Safety and tolerabilitywere assessed throughout the study. Main pharmacokinetic parameters of the fixedcombination were estimated for both, ivermectin [Cmax (mean, confidence interval): 86.40(30.42–39.23) ng/ml; AUC0-72 (mean, CI): 1,040 (530–1,678) ng·h/mL; tmax (median, min.,and max.); 4.50 (2.50–5.50)] and albendazole [Cmax (mean, CI): 22.27 (1.89–111.78) ng/ml; AUC0-72 (mean, CI): 94.65 (11.65–507.78) ng·h/mL; tmax (median, min., and max.):2.50 (1.00–12.00) h]. The 90% confidence interval of the geometric mean ratiosdemonstrated the bioequivalence in the case of ivermectin (Cmax: 110.68%–120.49%;AUC0-72: 110.46%–119.60%) but not in the case of albendazole (Cmax: 53.10%–70.34%;AUC0-72: 61.13%–76.54%). The pharmacokinetic profile of a new fixed-dose combinationof ivermectin and albendazole was characterized. The bioequivalence versus the referenceivermectin was demonstrated, though bioequivalence versus albendazole was not shown.The three medications analyzed were well tolerated. The results allow the advancement tothe next phase of the clinical program to demonstrate efficacy and safety in patientsaffected by soil-transmitted helminths.