Novel Compound Induces Erythropoietin Secretion through Liver Effects in Chronic Kidney Disease Patients and Healthy Volunteers
| Autor: | Hironori Yamasaki, Hirotaka Watase, Noriko Takayama, Tomohiro Sugimoto, Fumihiko Sato, Aya Shinfuku, Sota Kato, Takumi Numazaki, Toshiharu Shimazaki, Jinsei Maruyama, Masaru Mutoh, Masanori Fujiwara, Yasunori Kawakita |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adult Male medicine.medical_specialty Dihydropyridines Anemia Pyridines medicine.medical_treatment 030232 urology & nephrology Renal function Administration Oral Kidney Gastroenterology Hypoxia-Inducible Factor-Proline Dioxygenases 03 medical and health sciences Young Adult 0302 clinical medicine Pharmacokinetics Renal Dialysis Internal medicine medicine Humans Renal Insufficiency Chronic Erythropoietin Dialysis Aged Dose-Response Relationship Drug business.industry Middle Aged medicine.disease Healthy Volunteers 030104 developmental biology Treatment Outcome Liver Nephrology Pharmacodynamics Area Under Curve Female Hemodialysis Original Report: Patient-Oriented Translational Research business Kidney disease medicine.drug Glomerular Filtration Rate |
| Zdroj: | American journal of nephrology. 48(3) |
| ISSN: | 1421-9670 |
| Popis: | Background: TP0463518 is a novel hypoxia-inducible factor prolyl hydroxylase inhibitor developed to aid in the treatment of anemia associated with chronic kidney disease (CKD) and is expected to increase erythropoietin (EPO) derived from liver. Two phase I studies were conducted in healthy volunteers (HV) and CKD patients undergoing hemodialysis (i.e., HD patients) or those not undergoing dialysis (i.e., ND patients). Methods: Pharmacokinetics, pharmacodynamics, and safety profiles of TP0463518 were assessed. Forty HV received single oral doses of TP0463518 at 3, 6, 11, 20, and 36 mg or placebo. Twenty ND patients received single doses of TP0463518 at 1, 6, and 11 mg and 9 HD patients received TP0463518 at 1 and 11 mg doses. To identify the source organ of EPO, glycosylation patterns were determined using percentage migrated isoform (PMI) values. Results: Declining renal function slowed elimination of TP0463518 and increased the mean AUC0–∞. ∆Emax of serum EPO in 11-mg groups of HV, ND patients, and HD patients were 24.37 ± 11.37, 201.57 ± 130.34, and 1,324.76 ± 1,189.24 mIU/mL respectively. A strong correlation was observed between logarithm conversions of ∆Emax and AUC0–∞ with correlation coefficients of 0.945. PMI values of blood after TP0463518 administration were elevated to similar or higher levels in comparison with those of umbilical cord blood, which mainly contains liver-derived EPO. Conclusions: TP0463518 induced dose-dependent EPO production, mainly derived from the liver in HV and CKD patients. These results suggest that TP0463518 is a new strategy for treating anemia in CKD, which can be used regardless of renal functions. |
| Databáze: | OpenAIRE |
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