摘要
      GLPG1972/S201086是一种崩解蛋白和金属蛋白酶与血小板反应蛋白-5（ADAMTS-5）抑制剂，正在开发成为骨关节炎疾病的改良疗法。我们在3项随机、双盲、安慰剂对照的1期试验中报告了GLPG1972的安全性、耐受性、药代动力学和药效学（血浆/血清ARGS聚集蛋白聚糖新表位片段[ARGS]的周转）。研究A是首次对健康男性（N=41；NCT02612246）进行单次（≤2100 mg[禁食]和300 mg[喂食]）和多次（≤1050 mg每日一次[喂食]；14天）口服（溶液）递增剂量的人体试验。研究B调查了患有骨关节炎的男性和女性参与者（N=30；NCT03311009）的多次口服（片剂）剂量的GLPG1972（≤300mg，每日一次[喂食]；4周）。研究C调查了健康日本和白人男性（N=88）的单次（日语：≤1500 mg；白人：300 mg[禁食]）和多次（日语，≤1050 mg，每天一次；白人，300 mg，每天[喂食]；14天）口服（片剂）GLPG1972递增剂量。GLPG1972的药代动力学特征在健康参与者和骨关节炎参与者之间相似，具有低到中等的个体间变异性。GLPG1972被迅速吸收（达到最大浓度的中位时间为4小时），并以≈10小时的平均表观终末消除半衰期被消除。给药后2天内达到稳定状态，累积量最小。300mg GLPG1972后的稳态血浆暴露在人群之间没有或有轻微差异。研究之间的血浆浓度-时间曲线下面积（56.8-67.6μg·h/mL）和达到最大浓度的时间（4小时）相似。GLPG1972（24小时）的尿排泄量较低（<11%）。与安慰剂相比，在所有时间点，多次给药显著降低了ARGS水平。GLPG1972在所有剂量下通常耐受性良好。
Abstract
GLPG1972/S201086 is a disintegrin and metalloproteinase with thrombospondin motif-5 (ADAMTS-5) inhibitor in development as an osteoarthritis disease-modifying therapy. We report the safety, tolerability, pharmacokinetics, and pharmacodynamics (turnover of plasma/serum ARGS-aggrecan neoepitope fragments [ARGS]) of GLPG1972 in 3 randomized, double-blind, placebo-controlled phase 1 trials. Study A, a first-in-human trial of single (≤2100 mg [fasted] and 300 mg [fed]) and multiple (≤1050 mg once daily [fed]; 14 days) ascending oral (solution) doses, investigated GLPG1972 in healthy men (N = 41; NCT02612246). Study B investigated multiple ascending oral (tablet) doses of GLPG1972 (≤300 mg once daily [fed]; 4 weeks) in male and female participants with osteoarthritis (N = 30; NCT03311009). Study C investigated single (Japanese: ≤1500 mg; White: 300 mg [fasted]) and multiple (Japanese, ≤1050 mg once daily; White, 300 mg once daily [fed]; 14 days) ascending oral (tablet) doses of GLPG1972 in healthy Japanese and White men (N = 88). The pharmacokinetic profile of GLPG1972 was similar between healthy participants and participants with osteoarthritis, with low to moderate interindividual variability. GLPG1972 was rapidly absorbed (median time to maximum concentration, 4 hours), and eliminated with a mean apparent terminal elimination half-life of ≈10 hours. Steady state was achieved within 2 days of dosing, with minimal accumulation. Steady-state plasma exposure after 300 mg of GLPG1972 showed no or minor differences between populations. Area under the plasma concentration–time curve (56.8-67.6 μg · h/mL) and time to maximum concentration (4 hours) were similar between studies. Urinary excretion of GLPG1972 (24 hours) was low (<11%). Multiple dosing significantly reduced ARGS levels vs baseline at all time points for all doses vs placebo. GLPG1972 was generally well tolerated at all doses.

https://accp1.onlinelibrary.wiley.com/doi/full/10.1002/cpdd.1042