daprodustat,GSK1278863

Absorption

Daprodustat exposure generally increases in a dose-proportional manner over the range of therapeutic doses. Steady-state concentrations are achieved within 24 hours of dosing. Following oral administration, daprodustat is readily absorbed with a median time to peak concentration (Tmax) in healthy subjects ranging from one to four hours. The absolute bioavailability of daprodustat is 65%. Administration of daprodustat with a high-fat or high-calorie meal did not significantly alter daprodustat exposure compared to administration in the fasted state.

Toxicity

Headache and gastrointestinal adverse reactions (e.g., nausea) may be seen with acute overdose with daprodustat. There is no specific antidote. Hemodialysis will not substantially remove daprodustat because it is highly protein bound.

The Uses of daprodustat,GSK1278863

Daprodustat is a novel HIF (Hypoxia inducible factor)-prolyl hydroxylase inhibitor.

Indications

Daprodustat is a hypoxia-inducible factor prolyl hydroxylase (HIF PH) inhibitor indicated for the treatment of anemia due to chronic kidney disease in adults who have been receiving dialysis for at least four months.
The US prescribing information for daprodustat indicates that the drug was not shown to improve quality of life, fatigue, or patient well-being. It is not advised to be used as a substitute for transfusion in patients requiring immediate correction of anemia. It is also not indicated in patients not on dialysis.

Background

Daprodustat is a small-molecule hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) inhibitor that was developed by GSK. Patients with CKD cannot induce erythropoietin (EPO) production in response to hypoxia or anemia. As a potent inhibitor of PHD1, PHD2 and PHD3 (≥?1000-fold selectivity), daprodustat stabilizes cellular HIF1α and HIF2α and the induces erythropoiesis. A phase 3 clinical trial (NCT02879305) found that in patients with CKD undergoing dialysis, daprodustat was non-inferior to erythropoiesis-stimulating agents regarding the change in the hemoglobin level from baseline and cardiovascular outcomes.
In June 2020, daprodustat was first approved in Japan for the treatment of renal anemia. On October 2022, the FDA Cardiovascular and Renal Drugs Advisory Committee (CRDAC) supported that the benefit of treatment with daprodustat outweighs the risks for adult dialysis patients with anemia of CKD but not for non-dialysis patients with anemia of CKD. On February 1, 2023, daprodustat was fully approved by the FDA as the first oral treatment for anemia caused by chronic kidney disease in patients on dialysis. The drug is currently under EMA review.

Biological Activity

daprodustat (gsk1278863) is a hif-prolyl hydroxylase inhibitor.hypoxia stimulates erythropoietin (epo) release through accumulation of hypoxia-inducible factor 1α (hif-1α), resulting in an increase of erythrocyte production by the bone marrow. hif-prolyl hydroxylase inhibitors have been used to selectively activate the phd-signaling pathway, leading to the stabilization of hifα subunits, which can affect the transcription of hif-responsive genes.

Pharmacokinetics

Daprodustat is Daprodustat increases endogenous erythropoietin in a dose-dependent manner within six to eight hours after administration. With repeated doses, peak increases in reticulocyte counts occurred in seven to 15 days, with subsequent increases in red blood cell production. New hemoglobin steady-state levels are reached several weeks (approximately four weeks in ESA-users and approximately 16-20 weeks in ESA-non-users) after initial administration.
Daprodustat also increased serum transferrin and total iron binding capacity (TIBC) and decreased serum ferritin, transferrin saturation, and hepcidin when administered for 52 weeks in adults on dialysis with anemia due to CKD.

in vitro

in-vitro biotransformation data indicated that gsk1278863 was primarily metabolized by cyp2c8 [1].

Metabolism

In vitro, daprodustat is primarily metabolized by CYP2C8 (95% contribution), with a minor contribution by CYP3A4 (5%). Following oral or intravenous administration of radiolabeled daprodustat to healthy adults, approximately 40% of the total circulating radioactivity in plasma was daprodustat, and the remaining 60% was metabolites.
The parent drug is the principal circulating component in plasma. Of the six metabolites of daprodustat that were characterized, the major metabolites were M2 (GSK2391220), M3 (GSK2506104), and M13 (GSK2531401), with each metabolite accounting for more than 10% of circulating radioactivity in plasma. In humans, each metabolite circulates primarily as a single stereoisomeric form. In vitro and non-clinical studies suggest that these identified metabolites have a comparable pharmacological activity to the parent drug; however, the extent of the pharmacological contribution of each metabolite is unknown.

References

[1] hara k,takahashi n,wakamatsu a,caltabiano s. pharmacokinetics, pharmacodynamics and safety of single, oral doses of gsk1278863, a novel hif-prolyl hydroxylase inhibitor, in healthy japanese and caucasian subjects. drug metab pharmacokinet.2015 dec;30(6):410-8.
[2] brigandi ra,johnson b,oei c,et al. a novel hypoxia-inducible factor-prolyl hydroxylase inhibitor (gsk1278863) for anemia in ckd: a 28-day, phase 2a randomized trial. am j kidney dis.2016 jun;67(6):861-71.