Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy Japanese and non-Asian male subjects
| Autor: | Jeffrey N. Miner, Zancong Shen, Jesse Hall, Michael Gillen, Caroline A. Lee, Shakti Valdez, Sha Liu |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Pyridines Administration Oral Pharmaceutical Science Gastroenterology chemistry.chemical_compound 0302 clinical medicine serum urate Drug Discovery Single-Blind Method Hyperuricemia selective uric acid reabsorption inhibitor Original Research Middle Aged Uricosuric Agents Healthy Volunteers Kidney Tubules Tolerability Area Under Curve pharmacokinetics Half-Life Adult medicine.medical_specialty Metabolic Clearance Rate Cmax Naphthalenes Placebo Models Biological Drug Administration Schedule Young Adult 03 medical and health sciences Asian People Pharmacokinetics Internal medicine pharmacodynamics urinary uric acid medicine Humans 030203 arthritis & rheumatology Pharmacology Drug Design Development and Therapy business.industry medicine.disease Renal Reabsorption Uric Acid Gout Renal Elimination 030104 developmental biology chemistry Pharmacodynamics Uric acid Propionates business |
| Zdroj: | Drug Design, Development and Therapy |
| ISSN: | 1177-8881 |
| DOI: | 10.2147/dddt.s152659 |
| Popis: | Jesse Hall,1 Michael Gillen,2 Sha Liu,1 Jeffrey N Miner,1 Shakti Valdez,1 Zancong Shen,1 Caroline Lee1 1Ardea Biosciences, Inc., San Diego, CA, USA; 2AstraZeneca, Gaithersburg, MD, USA Purpose: Verinurad (RDEA3170) is a selective uric acid reabsorption inhibitor in clinical development for treatment of gout and asymptomatic hyperuricemia. This study evaluated verinurad pharmacokinetics, pharmacodynamics, and tolerability in healthy Japanese and non-Asian adult male subjects.Methods: This was a Phase I, randomized, single-blind, placebo-controlled study. Panels of 8 Japanese subjects were randomized to receive oral verinurad (2.5–15 mg) or placebo administered as a single dose in a fasted and fed state and as once-daily doses for 7 days in a fed state. Eight non-Asian subjects received verinurad 10 mg as a single dose (fasted and fed) and multiple doses in the fed state. Serial plasma/serum and urine samples were assayed for verinurad and uric acid. Safety was assessed by adverse events and laboratory data.Results: Of 48 randomized subjects, 46 (Japanese, 39; non-Asian, 7) completed the study. Following single or multiple doses in Japanese subjects, maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) increased in a near dose-proportional manner. Time to Cmax (Tmax) was ~1.25–2.0 hours with fasting. A moderate-fat meal delayed Tmax (range 3.0–5.0 hours) and had a variable effect on AUC (0%–97% increase) and Cmax (0%–26% increase) across the dose groups. Following multiple verinurad 10 mg doses, Cmax and AUC were 38% and 23% higher, respectively, in Japanese vs non-Asian subjects, largely due to body weight differences. Mean reduction of serum urate following multiple verinurad 10 mg doses was 46% and 44% after 24 hours in Japanese and non-Asian subjects, respectively. Verinurad was well tolerated at all doses.Conclusion: Verinurad monotherapy lowered serum urate and was well tolerated in both healthy Japanese and non-Asian males, while small differences in plasma pharmacokinetics were observed. These data support further evaluation of once-daily verinurad as a treatment for gout and asymptomatic hyperuricemia. Keywords: pharmacokinetics, pharmacodynamics, selective uric acid reabsorption inhibitor, serum urate, urinary uric acid |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|