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1.
Am J Nephrol ; 48(3): 157-164, 2018.
Article in English | MEDLINE | ID: mdl-30176654

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.


Subject(s)
Anemia/drug therapy , Dihydropyridines/pharmacology , Erythropoietin/metabolism , Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors , Liver/drug effects , Pyridines/pharmacology , Renal Insufficiency, Chronic/complications , Administration, Oral , Adult , Aged , Anemia/blood , Area Under Curve , Dihydropyridines/therapeutic use , Dose-Response Relationship, Drug , Female , Glomerular Filtration Rate , Healthy Volunteers , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism , Kidney/metabolism , Kidney/physiopathology , Liver/metabolism , Male , Middle Aged , Pyridines/therapeutic use , Renal Dialysis , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/therapy , Treatment Outcome , Young Adult
2.
Biol Pharm Bull ; 40(8): 1207-1218, 2017.
Article in English | MEDLINE | ID: mdl-28769002

ABSTRACT

Luseogliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor that reduces hyperglycemia in type 2 diabetes mellitus (T2DM) by promoting urinary glucose excretion (UGE). A clinical pharmacology study conducted in Japanese patients with T2DM confirmed dose-dependency of UGE with once-daily administration of luseogliflozin; however, the reason for sustained UGE after plasma luseogliflozin decreased was unclear. To elucidate the effect of inhibition rate constants, Kon and Koff, and to explain the sustained UGE, a pharmacokinetic-pharmacodynamic (PK-PD) model was built based on the mechanisms of glucose filtration in the glomerulus and reabsorption in the renal proximal tubule of kidney as well as the kinetics of competitive inhibition of SGLT1/2 and inhibition rate constants of SGLT2, by using UGE and plasma glucose levels and luseogliflozin concentrations. This acquired population PK-PD model adequately described the sustained UGE and the estimated population means of the inhibition constant for SGLT2 (Ki2) and inhibition-rate constants for SGLT2 (Kon and Koff) were 0.31- and 3.6-fold lower or higher than the in vitro values. Because the dissociation half-time of luseogliflozin from SGLT2 calculated from Koff, 6.81 h, was consistent with the value in vitro, we considered that the sustained UGE could be explained by the long dissociation half-time. Moreover, by calculating the SGLT2 inhibition ratio using the model, we discuss other properties of the UGE time course after luseogliflozin administration.


Subject(s)
Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/pharmacokinetics , Models, Biological , Sorbitol/analogs & derivatives , Adult , Aged , Asian People , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/metabolism , Female , Glucose/metabolism , Humans , Hypoglycemic Agents/blood , Kidney Glomerulus/metabolism , Kidney Tubules, Proximal/metabolism , Male , Middle Aged , Sodium-Glucose Transporter 2/metabolism , Sodium-Glucose Transporter 2 Inhibitors , Sorbitol/blood , Sorbitol/pharmacokinetics , Sorbitol/pharmacology
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