Open AccessPharmacokinetic/pharmacodynamic modeling and simulation of dotinurad, a novel uricosuric agent, in healthy volunteers
Author(s) -
Motoki Keisuke,
Igarashi Takako,
Omura Koichi,
Nakatani Hiroshi,
Iwanaga Takashi,
Tamai Ikumi,
Ohashi Tetsuo
Publication year - 2019
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.533
Subject(s) - pharmacokinetics , pharmacodynamics , pharmacology , renal physiology , chemistry , reabsorption , absorption (acoustics) , uricosuric , medicine , uric acid , kidney , hyperuricemia , physics , acoustics
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.