A Single‐Dose, Open‐Label, Randomized, Two‐Way Crossover Study in Healthy Japanese Participants to Evaluate the Bioequivalence and the Food Effect on the Pharmacokinetics of Daprodustat

Abstract

Daprodustat is a prolyl hydroxylase inhibitor that stimulates erythropoiesis in a manner similar to the natural response to hypoxia, whereby inhibition of hypoxia inducible factor (HIF) prolyl-4-hydroxylases by daprodustat ultimately results in increased levels of HIF-responsive genes. Daprodustat is under development as an emerging new class of agents for the treatment of anemia associated with chronic kidney disease (CKD). This was a single-center, single-dose, open-label, randomized, 2-way crossover study in healthy Japanese male participants consisting of 2 parts. The primary objective was to evaluate the bioequivalence (BE) between daprodustat tablet strengths (part 1) and to evaluate the food effect on the pharmacokinetics (PK) of daprodustat (part 2). A total of 64 healthy Japanese male participants were enrolled; 52 participants were included in part 1 and 12 in part 2. BE was demonstrated between the daprodustat 2-mg tablet and the daprodustat 4-mg tablet. A standard CKD meal did not have a large effect on the PK parameters of daprodustat after a single oral dose of daprodustat 4 mg. Administration of single oral doses of daprodustat 4 mg was generally well tolerated in the healthy Japanese participants, and no new safety signals were identified without regard to food.

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

“…Plasma daprodustat data were collected as previously described 17,19 and calculated via standard noncompartmental analysis with WinNonlin 6.3 or higher (Certara, Princeton, NJ). All calculations were based on actual sampling times.…”

“…The pharmacokinetic (PK) profile of daprodustat is similar in the healthy adult and CKD populations as the maximum observed drug concentration (C max ), area under concentration‐time curve (AUC), and t max have been shown to be comparable in both groups 18 . Coadministration of a single 100 mg daprodustat dose with a high‐fat, high‐calorie meal resulted in an 11% and 31% decrease in daprodustat AUC and C max , respectively, and a 1‐hour mean delay of t max relative to fasted administration while dosing 4 mg of daprodustat 30 minutes after a CKD meal (500–700 kcal, composed of 12–16 g of protein, 1–2 g of salt, and up to 500 mg of potassium) resulted in a 9% and 11% decrease in daprodustat AUC and C max , respectively, and a 1‐hour mean delay of t max relative to fasted administration 19,20 . Daprodustat is extensively metabolized by cytochrome P450 2C8, is highly absorbed across the gastrointestinal tract following oral administration, and is mainly cleared through hepatobiliary and fecal routes 16,20 .…”

“…a 1-hour mean delay of t max relative to fasted administration while dosing 4 mg of daprodustat 30 minutes after a CKD meal (500-700 kcal, composed of 12-16 g of protein, 1-2 g of salt, and up to 500 mg of potassium) resulted in a 9% and 11% decrease in daprodustat AUC and C max , respectively, and a 1-hour mean delay of t max relative to fasted administration. 19,20 Daprodustat is extensively metabolized by cytochrome P450 2C8, is highly absorbed across the gastrointestinal tract following oral administration, and is mainly cleared through hepatobiliary and fecal routes. 16,20 As daprodustat is a cytochrome P450 2C8 substrate, a significant interaction was observed with gemfibrozil, and a lesser interaction was observed with trimethoprim.…”

Daprodustat: First Approval

“…Daprodustat exhibited linear pharmacokinetics after single-dose administration over the dose range 10-100 mg. Following administration of a single oral 4 mg dose of daprodustat, the median time to peak plasma concentration of daprodustat (t max ) was reached in 1.75 h (fasting state) or 2.75 h (after a meal) (NCT03493386) [7,10]. Daprodustat exposure was slightly lower when the drug was administered after a standard CKD meal, as indicated by a 9% decrease in the area under the concentration-time curve (AUC) from 0 to infinity and an 11% decrease in the peak plasma concentration (C max ) (NCT03493386) [7,10].…”

“…The mean urinary excretion of oral daprodustat was < 0.05% of the dose [ 7 ]. The elimination half-life of oral daprodustat after a single 4 mg dose in healthy subjects was 3.24 h (fasting state) or 3.22 h (after a meal) (NCT03493386) [ 7 , 10 ].…”