Clinical Pharmacokinetics of Daprodustat: Results of an Absorption, Distribution, and Excretion Study With Intravenous Microtracer and Concomitant Oral Doses for Bioavailability Determination

Abstract

Daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being investigated for treatment of anemia in chronic kidney disease. This phase 1, nonrandomized, 2-period, crossover study in 6 healthy men characterized the absorption, distribution, and excretion of daprodustat when administered as oral and intravenous (IV) doses of unlabeled and radiolabeled daprodustat ([ 14 C]-GSK1278863). Tolerability and pharmacokinetic properties of daprodustat, and its 6 metabolites in the systemic circulation, were also evaluated. The mean recovery of radiolabeled daprodustat was ≈95% by day 5, with the majority in feces and minor renal elimination, indicating that daprodustat and metabolites are primarily eliminated via hepatobiliary and fecal routes. Approximately 40% of total circulating radioactivity in plasma following both IV and oral administration was daprodustat; thus, 60% was attributed to metabolites. It was estimated that ≈80% of daprodustat was absorbed across the gastrointestinal tract, and ≈18% cleared by hepatic extraction. Pharmacokinetics were essentially dose proportional, with moderate (≈66%) oral tablet bioavailability. Following IV administration, daprodustat plasma clearance (19.3 L/h) and volume of distribution (14.6 L) were low, suggesting low tissue distribution outside systemic circulation with likely low penetration into tissues. Daprodustat was generally well tolerated, with no deaths or serious or significant adverse events reported.

Pharmacokinetics of Daprodustat and Metabolites in Individuals with Normal and Impaired Hepatic Function

“…Additionally, preclinical repeat‐dose toxicity studies suggest similar toxicologic profiles compared with daprodustat 19 . Characterization of the absorption, distribution, metabolism, and excretion showed low urine recovery of the parent drug, indicating that daprodustat and its metabolites are mainly eliminated via hepatobiliary and fecal routes 20,21 …”

“…19 Characterization of the absorption, distribution, metabolism, and excretion showed low urine recovery of the parent drug, indicating that daprodustat and its metabolites are mainly eliminated via hepatobiliary and fecal routes. 20,21 The primary objective of this study was to compare plasma pharmacokinetic (PK) parameters of daprodustat and its six predominant metabolites in participants with hepatic impairment versus healthy matched controls following oral administration of a single 6-mg dose of daprodustat. Secondary objectives were to investigate the pharmacodynamic effect (ie, EPO production) and tolerability following a single dose of daprodustat in this population.…”

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

“…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. 20,21 Additionally, daprodustat has been shown to be noninferior to erythropoiesis-stimulating agents with regard to safety and efficacy.…”

“…Clinical data have shown that daprodustat administered orally is rapidly absorbed, with time to maximum concentration (t max ) of 1–4 hours, and exhibits dose‐proportional increases in exposure 15–17 . 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 . As daprodustat is a cytochrome P450 2C8 substrate, a significant interaction was observed with gemfibrozil, and a lesser interaction was observed with trimethoprim 20,21 .…”