{"title":"单剂量和多剂量在中国健康成人体内的药代动力学和安全性研究。","authors":"Yun Liu, Qian Chen, Hui Sun, Cuiyuan Cai, Kotomi Kawamura, Rieko Kokan, Maiko Nomoto","doi":"10.1007/s40261-025-01496-x","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objectives: </strong>Dotinurad is a selective uricosuric drug for patients with gout with hyperuricemia. To our knowledge, this is the first study to evaluate the pharmacokinetics (PK) of dotinurad, following single and multiple oral doses in healthy Chinese adults.</p><p><strong>Methods: </strong>This single-center, open-label, parallel group, phase 1 study had 3 cohorts: A (1-mg single dose), B (single and multiple doses of 4 mg once daily for 7 days), and C (10-mg single dose). Dotinurad was administered on an empty stomach. Healthy nonsmoking Chinese adults aged 18-45 years with body mass index 19-24 k/m<sup>2</sup> and weight ≥ 50 kg were enrolled; Cohort B required serum urate ≥ 5.5 mg/dL at screening.</p><p><strong>Results: </strong>In total, 26 subjects were included. After single oral doses of 1, 4, and 10 mg, mean ± standard deviation (SD) plasma dotinurad concentration reached maximum observed plasma concentration (C<sub>max</sub>) of 104 ± 18.5, 365 ± 35.2, and 964 ± 101 ng/mL at 3.00-3.50 h, respectively. The mean ± SD terminal elimination phase half-life was 10.1 ± 1.26, 9.87 ± 1.47, and 10.9 ± 1.53 h for the 1, 4, and 10 mg doses, respectively; both area under the plasma concentration-time curve and C<sub>max</sub> increased in a dose-proportional manner across the 1-10-mg dose range. During once-daily doses for 7 days, steady state was reached by the 2nd day after the initiation of multiple dosing, with an average steady-state plasma concentration of 186 ± 31.8 ng/mL, indicating minimal accumulation. Treatment-emergent adverse events (TEAEs) occurred in four subjects (15.4%); all were mild and resolved without treatment. No dose-dependent TEAEs were observed.</p><p><strong>Conclusion: </strong>Single- and multiple-dose PK of dotinurad in healthy Chinese adults showed rapid absorption, rapid elimination, linear PK, and no accumulation with once-daily dosing. Dotinurad was well-tolerated during the 7-day treatment course.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov: NCT05278676.</p>","PeriodicalId":10402,"journal":{"name":"Clinical Drug Investigation","volume":" ","pages":""},"PeriodicalIF":2.7000,"publicationDate":"2025-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A Single- and Multiple-Dose Study to Characterize the Pharmacokinetics and Safety of Dotinurad in Healthy Chinese Adults.\",\"authors\":\"Yun Liu, Qian Chen, Hui Sun, Cuiyuan Cai, Kotomi Kawamura, Rieko Kokan, Maiko Nomoto\",\"doi\":\"10.1007/s40261-025-01496-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objectives: </strong>Dotinurad is a selective uricosuric drug for patients with gout with hyperuricemia. To our knowledge, this is the first study to evaluate the pharmacokinetics (PK) of dotinurad, following single and multiple oral doses in healthy Chinese adults.</p><p><strong>Methods: </strong>This single-center, open-label, parallel group, phase 1 study had 3 cohorts: A (1-mg single dose), B (single and multiple doses of 4 mg once daily for 7 days), and C (10-mg single dose). Dotinurad was administered on an empty stomach. Healthy nonsmoking Chinese adults aged 18-45 years with body mass index 19-24 k/m<sup>2</sup> and weight ≥ 50 kg were enrolled; Cohort B required serum urate ≥ 5.5 mg/dL at screening.</p><p><strong>Results: </strong>In total, 26 subjects were included. After single oral doses of 1, 4, and 10 mg, mean ± standard deviation (SD) plasma dotinurad concentration reached maximum observed plasma concentration (C<sub>max</sub>) of 104 ± 18.5, 365 ± 35.2, and 964 ± 101 ng/mL at 3.00-3.50 h, respectively. The mean ± SD terminal elimination phase half-life was 10.1 ± 1.26, 9.87 ± 1.47, and 10.9 ± 1.53 h for the 1, 4, and 10 mg doses, respectively; both area under the plasma concentration-time curve and C<sub>max</sub> increased in a dose-proportional manner across the 1-10-mg dose range. During once-daily doses for 7 days, steady state was reached by the 2nd day after the initiation of multiple dosing, with an average steady-state plasma concentration of 186 ± 31.8 ng/mL, indicating minimal accumulation. Treatment-emergent adverse events (TEAEs) occurred in four subjects (15.4%); all were mild and resolved without treatment. No dose-dependent TEAEs were observed.</p><p><strong>Conclusion: </strong>Single- and multiple-dose PK of dotinurad in healthy Chinese adults showed rapid absorption, rapid elimination, linear PK, and no accumulation with once-daily dosing. Dotinurad was well-tolerated during the 7-day treatment course.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov: NCT05278676.</p>\",\"PeriodicalId\":10402,\"journal\":{\"name\":\"Clinical Drug Investigation\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2025-10-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Drug Investigation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s40261-025-01496-x\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Drug Investigation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s40261-025-01496-x","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
A Single- and Multiple-Dose Study to Characterize the Pharmacokinetics and Safety of Dotinurad in Healthy Chinese Adults.
Background and objectives: Dotinurad is a selective uricosuric drug for patients with gout with hyperuricemia. To our knowledge, this is the first study to evaluate the pharmacokinetics (PK) of dotinurad, following single and multiple oral doses in healthy Chinese adults.
Methods: This single-center, open-label, parallel group, phase 1 study had 3 cohorts: A (1-mg single dose), B (single and multiple doses of 4 mg once daily for 7 days), and C (10-mg single dose). Dotinurad was administered on an empty stomach. Healthy nonsmoking Chinese adults aged 18-45 years with body mass index 19-24 k/m2 and weight ≥ 50 kg were enrolled; Cohort B required serum urate ≥ 5.5 mg/dL at screening.
Results: In total, 26 subjects were included. After single oral doses of 1, 4, and 10 mg, mean ± standard deviation (SD) plasma dotinurad concentration reached maximum observed plasma concentration (Cmax) of 104 ± 18.5, 365 ± 35.2, and 964 ± 101 ng/mL at 3.00-3.50 h, respectively. The mean ± SD terminal elimination phase half-life was 10.1 ± 1.26, 9.87 ± 1.47, and 10.9 ± 1.53 h for the 1, 4, and 10 mg doses, respectively; both area under the plasma concentration-time curve and Cmax increased in a dose-proportional manner across the 1-10-mg dose range. During once-daily doses for 7 days, steady state was reached by the 2nd day after the initiation of multiple dosing, with an average steady-state plasma concentration of 186 ± 31.8 ng/mL, indicating minimal accumulation. Treatment-emergent adverse events (TEAEs) occurred in four subjects (15.4%); all were mild and resolved without treatment. No dose-dependent TEAEs were observed.
Conclusion: Single- and multiple-dose PK of dotinurad in healthy Chinese adults showed rapid absorption, rapid elimination, linear PK, and no accumulation with once-daily dosing. Dotinurad was well-tolerated during the 7-day treatment course.
期刊介绍：
Clinical Drug Investigation provides rapid publication of original research covering all phases of clinical drug development and therapeutic use of drugs. The Journal includes:
-Clinical trials, outcomes research, clinical pharmacoeconomic studies and pharmacoepidemiology studies with a strong link to optimum prescribing practice for a drug or group of drugs.
-Clinical pharmacodynamic and clinical pharmacokinetic studies with a strong link to clinical practice.
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-Studies focusing on the application of drug delivery technology in healthcare.
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