Comparison of Two Manufacturing Processes of Daprodustat for Bioequivalence and Dissolution in Healthy Volunteers: A Randomized Crossover Study

AbstractDaprodustat, an orally bioavailable hypoxia-inducible factor –prolyl hydroxylase enzyme inhibitor, has recently completed phase 3 clinical development for treating anemia of chronic kidney disease. Part A of this 2-part, randomized, double-blind, single-dose, cross-over study (NCT04640311) compared pharmacokinetic properties of a single oral dose of daprodu stat 4 mg tablets manufactured via twin-screw wet granulation (process 1) to 2 sets of 4 mg tablets manufactured via high-shear wet granulation (process 2), to assess the impact of different dissolution profiles on pharmacokinetics. Part B assessed the bioequivalence of daprodustat tablets manufactu red via process 1 with tablets manufactured via process 2 at 5 different dose strengths (1, 2, 4, 6, and 8 mg). In part A, mean plasma concentrations of daprodustat were comparable over a 24-hour period despite differences in manufacturing processes and dissolution profiles. In part B, the 90% conf idence intervals of the ratios of the least squared means for area under the concentration-time curve and maximum observed plasma concentration fell within the 0.8–1.25 bioequivalence range for all doses, except for maximum observed plasma concentration at 8 mg. A prespecified sensitivity analysi s jointly assessing all doses showed bioequivalence for all doses tested. No new safety concerns for daprodustat were identified.
Source: Clinical Pharmacology in Drug Development - Category: Drugs & Pharmacology Authors: Tags: Original Article Source Type: research