Pharmacokinetic/pharmacodynamic modeling and simulation of dotinurad, a novel uricosuric agent, in healthy volunteers

• Main Authors: Keisuke Motoki, Takako Igarashi, Koichi Omura, Hiroshi Nakatani, Takashi Iwanaga, Ikumi Tamai, Tetsuo Ohashi
• Format: Article
• Language: English
• Published: Wiley 2019-12-01
• Series: Pharmacology Research & Perspectives
• Subjects: dotinurad; PK/PD model; URAT1; uric acid; uricosuric agent
• Online Access: https://doi.org/10.1002/prp2.533

Abstract 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 (Emax) model was selected as the PD model of dotinurad on renal urate reabsorption, resulting in an estimated Emax 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.