Novel Compound Induces Erythropoietin Secretion through Liver Effects in Chronic Kidney Disease Patients and Healthy Volunteers

Abstract

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.

Keywords: Anemia; Erythropoietin; Hypoxia-inducible factor-inhibitor; TP0463518.

The Author(s). Published by S. Karger AG, Basel.

Figures

Fig. 1

Mean plasma concentration-time profiles of TP0463518 (mean ± SD) in HV (a), ND patients (b), and HD patients (c) for linear-scale and in the 11-mg group in each subj ect group for semi-logarithmic scale (d). Follow-up 1 in HD patients was treated as 72 h. TP0463518 was administered under fasting state in (a) and after meal in (b–d). HD, CKD patients undergoing hemodialysis; H V, healthy volunteers; ND, CKD patients not undergoing dialysis.

Fig. 2

Changes in mean serum EPO concentration over time (mean ± SD) in HV (a), ND patients (b), and HD patients (c) for linear-scale and in the 11-mg groups in each subject group for semi-logarithmic scale (d). Follow-up 1 in HD patients was treated as 72 h. EPO, erythropoietin; HD, CKD patients undergoing hemodialysis; HV, healthy volunteers; ND, CKD patients not undergoing dialysis.

Fig. 3

Relationship between PK parameters [Cmax (a) and AUC0–∞ (b) and PD parameter (δEmax) across the studies. AUC0–∞, area under the concentration-time curve extrapolated to infinity; Cmax, the maximum concentration; Emax, the maximum serum EPO concentrations; HD, CKD patients undergoing hemodialysis; HV, healthy volunteers; ND, CKD patients not undergoing dialysis.

Fig. 4

The EPO glycosylation pattern determined by PMI (mean ± SD) in the HV (a) and CKD studies (b). HD, CKD patients undergoing hemodialysis; HV, healthy volunteers; ND, CKD patients not undergoing dialysis; PMI, percentage of migrated isoform.