Chemical formula: C₁₉H₂₇N₃O₆ Molecular mass: 393.19 g/mol PubChem compound: 91617630
Daprodustat is a reversible inhibitor of HIF-PH1, PH2 and PH3 (IC50 in the low nM range). This activity results in the stabilization and nuclear accumulation of HIF-1α and HIF-2α transcription factors, leading to increased transcription of the HIF-responsive genes, including erythropoietin.
Daprodustat increases endogenous erythropoietin in a dose-dependent manner within 6 to 8 hours after administration. With repeat doses, peak increases in reticulocyte counts occur between 7 and 15 days, with subsequent increases in red blood cell production. New hemoglobin steady-state levels are reached several weeks (approximately 4 weeks in ESA-users and approximately 16-20 weeks in ESA-non-users) after initial administration.
Daprodustat 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.
At a dose 10 times the maximum recommended dose, daprodustat does not prolong the QTc interval to any clinically relevant extent.
Daprodustat exposure generally increases in a dose-proportional manner over the range of approved doses. Steady-state concentrations are achieved within 24-hours of dosing.
Following oral administration, daprodustat is readily absorbed with median time to peak concentration (Tmax) in healthy subjects ranging from 1 hour to 4 hours. The absolute bioavailability of daprodustat is 65%. Administration of daprodustat with a high fat/high calorie meal did not significantly alter daprodustat exposure compared to administration in the fasted state.
Daprodustat has an approximately equal distribution between plasma and blood cells (blood:plasma ratio of 1.23). Following intravenous dosing, the volume of distribution at steady-state in healthy subjects is 14.3 L. In vitro, plasma protein binding of daprodustat is >99%.
The terminal elimination half-life of daprodustat is approximately 1 hour to 4 hours.
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.
In patients treated with daprodustat, the parent drug is the principal circulating component in plasma. Three metabolites, each accounting for more than 10% of circulating drug-related material, have been identified; in vitro and non-clinical data suggest that each may contribute to the pharmacologic response in vivo; however, the extent of this contribution is unknown.
Mean clearance from plasma was 18.9 L/h, which correlates to blood clearance of 15 L/h and equates to a hepatic extraction of approximately 18%.
Within seven days of an oral dose of radiolabeled daprodustat, 74% of the radioactivity was recovered in the feces, and 21% in the urine. Approximately 99.5% of the dose was excreted as oxidative metabolites, with the rest accounted for by daprodustat.
Population pharmacokinetic analyses in adults with CKD (22 years to 93 years) showed that age did not influence the pharmacokinetics of daprodustat.
The steady-state exposure of daprodustat is similar in patients with normal renal function and those with varying degrees of renal impairment; daprodustat exposure is not significantly impacted by hemodialysis or peritoneal dialysis. The systemic exposure of daprodustat metabolites was higher in patients with Stage 3 to 5 CKD compared to those with normal renal function. Exposures of metabolites were higher on non-dialysis days compared to dialysis days.
Following administration of a single daprodustat 6 mg dose, mean daprodustat Cmax and AUC increased by 2-fold and unbound exposure increased by 2.3-fold in subjects with moderate hepatic impairment (Child‑Pugh Class B) compared to subjects with normal hepatic and renal function. For those with mild hepatic impairment (Child‑Pugh Class A), mean daprodustat Cmax was similar while AUC increased by 1.5-fold and unbound Cmax and AUC increased by 1.6 and 2.2-fold, respectively, compared to subjects with normal hepatic and renal function. The effect of severe hepatic impairment (Child‑Pugh Class C) on the pharmacokinetics of daprodustat is unknown as there have been no studies of daprodustat in patients with severe hepatic impairment.
Effect of CYP2C8 Inhibitors on the Pharmacokinetics of Daprodustat:
The concomitant administration of gemfibrozil 600 mg twice a day for 5 days (strong CYP2C8 inhibitor) with a single 100 mg dose of daprodustat on Day 4 of gemfibrozil administration resulted in an 18.6‑fold increase in AUC(0-∞) and a 3.9-fold increase in Cmax of daprodustat.
The concomitant administration of trimethoprim 200 mg twice a day for 5 days (CYP2C8 weak inhibitor) and 25 mg single dose of daprodustat on Day 4 of trimethoprim administration resulted in a 1.5-fold increase in AUC(0-∞) and a 1.3‑fold increase in Cmax of daprodustat.
Daprodustat AUC and Cmax are expected to increase at least 4-fold and 3-fold, respectively, following concomitant administration of daprodustat with clopidogrel 75 mg once daily (moderate CYP2C8 inhibitor).
Following 4 weeks of daprodustat dosing, hemoglobin changes from baseline were similar in subjects with and without concomitant use of clopidogrel.
Effect of Daprodustat on the Pharmacokinetics of Other Drugs:
Clinical drug interaction studies showed that daprodustat inhibition of CYP2C8 and OATP1B1/OATP1B3 demonstrated no clinically significant effect on pioglitazone (CYP2C8 substrate) or rosuvastatin (OATP1B1/OATP1B3 substrate) Cmax or AUC.
Some oxidative metabolites of daprodustat are substrates of Organic Anion Transporter (OAT)1 or OAT3; however, the clinical significance of this is unknown. Daprodustat is a substrate of Breast Cancer Resistance Protein (BCRP); however, the risk of significant drug interactions between daprodustat and BCRP inhibitors is considered low given the absorption and metabolism profile of daprodustat.
Daprodustat is not an inducer of CYP1A2, CYP2B6 and CYP3A4. Daprodustat is not an inhibitor of P-glycoprotein (P-gp) and BCRP.
Daprodustat is not a substrate of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and P-gp. The major metabolites are not substrates of OATP1B1, OATP1B3, OATP2B1, Organic Cation Transporter (OCT)1, OCT2, Multidrug and Toxin Extrusion (MATE)1 and MATE2-K. Daprodustat and its major metabolites are not inhibitors of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, OATP1B1, OATP1B3, OATP2B1, OCT1, OAT1, OAT3, OCT2, MATE1 and MATE2-K.
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