Galapagos NV, Mechelen, Belgium.
Galapagos SASU, Romainville, France.
Clin Pharmacol Drug Dev. 2022 Jan;11(1):112-122. doi: 10.1002/cpdd.1042. Epub 2021 Dec 2.
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.
GLPG1972/S201086 是一种在研的解整合素金属蛋白酶与凝血酶样 5（ADAMTS-5）抑制剂，作为一种骨关节炎的疾病修饰治疗药物。我们报告了 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]的转化），这是在 3 项随机、双盲、安慰剂对照的 1 期试验中进行的。研究 A 是一项单次（≤2100mg[空腹]和 300mg[进食]）和多次（≤1050mg 每日一次[进食]；14 天）递增口服（溶液）剂量的首次人体试验，研究了 GLPG1972 在健康男性中的情况（N=41；NCT02612246）。研究 B 研究了 GLPG1972 多次递增口服（片剂）剂量（≤300mg 每日一次[进食]；4 周）在男性和女性骨关节炎患者中的情况（N=30；NCT03311009）。研究 C 研究了 GLPG1972 在健康的日本男性和白人男性中的单次（日本：≤1500mg；白人：300mg[空腹]）和多次（日本：≤1050mg 每日一次；白人：300mg 每日一次[进食]；14 天）递增口服（片剂）剂量（N=88）。GLPG1972 在健康参与者和骨关节炎患者中的药代动力学特征相似，个体间的变异性较低且中等。GLPG1972 吸收迅速（中位达峰时间为 4 小时），平均表观终末消除半衰期约为 10 小时。给药后 2 天达到稳态，蓄积最小。300mg GLPG1972 稳态后，不同人群的血浆暴露面积无差异或差异较小。曲线下面积（56.8-67.6μg·h/mL）和达峰时间（4 小时）在各研究间相似。24 小时尿液排泄 GLPG1972（<11%）。与安慰剂相比，所有剂量在所有时间点均能显著降低 ARGS 水平。GLPG1972 在所有剂量下均具有良好的耐受性。
