Clinical pharmacokinetics of an amorphous solid dispersion tablet of elacridar.

Abstract

Elacridar is an inhibitor of the permeability glycoprotein (P-gp) and the breast cancer resistance protein (BCRP) and is a promising absorption enhancer of drugs that are substrates of these drug-efflux transporters. However, elacridar is practically insoluble in water, resulting in low bioavailability which currently limits its clinical application. We evaluated the in vitro dissolution and clinical pharmacokinetics of a novel amorphous solid dispersion (ASD) tablet containing elacridar. The dissolution from ASD tablets was compared to that from a crystalline powder mixture in a USP type II dissolution apparatus. The pharmacokinetics of the ASD tablet were evaluated in an exploratory clinical study at oral doses of 25, 250, or 1000mg in 12 healthy volunteers. A target Cmax was set at ≥200ng/mL based on previous clinical data. The in vitro dissolution from the ASD tablet was 16.9±3.7 times higher compared to that from a crystalline powder mixture. Cmax and AUC0-∞ increased linearly with dose over the explored range. The target Cmax of ≥200ng/mL was achieved at the 1000-mg dose level. At this dose, the Cmax and AUC0-∞ were 326±67ng/mL and 13.4±8.6·103ng·h/mL, respectively. In summary, the ASD tablet was well tolerated, resulted in relevant pharmacokinetic exposure, and can be used for proof-of-concept clinical studies.