Table 1.
Summary of the pharmacologic properties of hypoxia-inducible factor–prolyl hydroxylase inhibitors
| Variable | Daprodustat68,69 (GSK1278863) | Desidustat70 (ZYAN1) | Enarodustat71,72 (JTZ-951) | Molidustat68,73,74 (BAY 85-3934) | Roxadustat68,75 (FG-4592; ASP1517; AZD9941) | Vadadustat68,76 (AKB-6548; MT-6548) | |
|---|---|---|---|---|---|---|---|
| Pharmacodynamics | |||||||
| IC50, μmol/L | |||||||
| MALDI-TOF binding assay | PHD1: 1.50 PHD2: 2.87 PHD3: 0.61 |
PHD1: 1.45 PHD2: 1.85 PHD3: 0.72 |
PHD1: 1.40 PHD2: 1.26 PHD3: 1.32 |
PHD1: 0.84 PHD2: 2.30 PHD3: 0.26 |
|||
| In vitro assay in HepG2 cells | 11.2a | ||||||
| Fluorescent enzyme assay | PHD1: 0.016 PHD2: 0.061 PHD3: 0.101 |
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| Pharmacokinetics | |||||||
| Participants | Japan, n = 13b | Cauc, n = 12b | Cauc, n = 56b | Mixed,c n = 6d | Japan, n = 9b | Japan, n = 15b | Cauc, n = 8b |
| Dose, mg | 100 | 100 | 10–300 | 10 | 50 | 100 | 450 |
| AUC, μg·h/mle | 5.20f | 3.55f | 3.7–116.2 | 7.33f | 1.11 | 88.7f | 397f |
| Cmax, μg/mle | 2.32 | 1.60 | 0.6–17.9 | 0.986 | 0.56 | 10.6 | 52.6 |
| Tmax, hg | 1.50 | 1.50 | 1.25–3.00 | 0.5 | 0.75 | 2.0 | 2.0 |
| t½, he | 2.25 | 1.86 | 7.0–11.4 | 25.9h; 8.96i | 10.4 | 13.1 | 5.8j |
| CL/F, L/he | 21.70 | 31.4 | 2.1–2.9 | 1.52 | 45.1 | 1.18 | NR |
| CLR, L/he | NR | NR | NR | NR | 0.693 | 0.0261 | NR |
| Metabolizing enzymes | CYP2C8, major CYP3A4, minor |
NR | CYP2C8, CYP2C9, CYP3A4 | UGTs | CYP2C8, major | UGT1A9, major | |
AUC, area under the concentration-time curve; Cauc, Caucasian; CL/F, apparent oral clearance; CLR, renal clearance; Cmax, peak plasma concentration; CYP, cytochrome P450; IC50, 50% PHD inhibitory concentration; Japan, Japanese; MALDI-TOF, matrix-assisted laser desorption ionization–time of flight; NR, not reported; PHD, prolyl hydroxylase domain; t½, elimination half-life; Tmax, time to Cmax; UGT, uridine 5'-diphospho-glucuronosyltransferase.
PHD enzyme isoform not specified.
Single-dose oral administration in fasted, healthy volunteers.
Participants were either Caucasian (n = 1), Black (n = 4), or American Indian/Alaskan Native (n = 1).
Single-dose oral administration in patients with end-stage renal disease on maintenance hemodialysis.
Mean.
Reported as AUC from time 0 to infinity.
Median.
Terminal t½.
Effective t½.
Value of 7.8 in patients with hepatic impairment.