Pharmacokinetic/pharmacodynamic modeling and simulation of dotinurad, a novel uricosuric agent, in healthy volunteers
| Autor: | Tetsuo Ohashi, Ikumi Tamai, Hiroshi Nakatani, Keisuke Motoki, Koichi Omura, Takako Igarashi, Takashi Iwanaga |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male Administration Oral Absorption (skin) RM1-950 Pharmacology 030226 pharmacology & pharmacy Models Biological Drug Administration Schedule dotinurad 03 medical and health sciences chemistry.chemical_compound Young Adult 0302 clinical medicine Pharmacokinetics Oral administration Uricosuric Agent Healthy volunteers Humans Benzothiazoles General Pharmacology Toxicology and Pharmaceutics Dose-Response Relationship Drug Reabsorption Original Articles Uricosuric Agents uricosuric agent Healthy Volunteers Uric Acid Renal Elimination Neurology chemistry 030220 oncology & carcinogenesis Pharmacodynamics Uric acid Original Article Therapeutics. Pharmacology URAT1 PK/PD model Half-Life |
| Zdroj: | Pharmacology Research & Perspectives Pharmacology Research & Perspectives, Vol 7, Iss 6, Pp n/a-n/a (2019) |
| ISSN: | 2052-1707 |
| Popis: | This study aimed to investigate the pharmacokinetic and pharmacodynamic (PK/PD) profiles of dotinurad, a novel uricosuric agent, and to construct a PK/PD model to predict serum urate (SUA) levels after dotinurad administration in healthy men. PK/PD model was constructed using single‐dose study data considering the physiological features of urate handling. Model validation was performed by comparing the predicted SUA levels with the SUA levels in a multiple‐dose study. Dotinurad was absorbed rapidly, and its exposure increased proportionally in the tested dose ranges (0.5–20 mg) after a single‐dose administration. The PK model after oral administration was described using a one‐compartment model with first‐order absorption. Effects on SUA and renal urate excretion of dotinurad increased with dose escalation but were apparently saturable at a dose >5 mg. The simple maximal effect (E max) model was selected as the PD model of dotinurad on renal urate reabsorption, resulting in an estimated E max of 0.51. The plasma concentration at the half‐maximal effect of dotinurad was 196 ng/mL. Other PD parameters were calculated from the change in SUA level or urinary excretion of urate before and after dotinurad administration. The predicted SUA levels, using the PK/PD model, were well‐fitted with the observed values. The constructed PK/PD model of dotinurad appropriately described the profiles of dotinurad plasma concentrations and SUA level in multiple administration study. |
| Databáze: | OpenAIRE |
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