Shah Jaymin, Pillinger Michael H, Chan Elaine K, Lissin Dmitri
Scilex Holding Company, 960 San Antonio Rd, Palo Alto, CA, 94303, USA.
NYU Grossman School of Medicine, New York, NY, USA.
Rheumatol Ther. 2025 Jun 2. doi: 10.1007/s40744-025-00772-8.
Patients receiving the standard prophylaxis dose of colchicine for gout flares are at increased risk for developing toxicity if there are pre-existing renal impairment or drug-drug interactions. Guidelines recommend exercising caution, deferring dose adjustment to the clinician's discretion.
Pharmacokinetic study data for colchicine oral solution in healthy subjects was used to build a pharmacokinetic model. Using the derived pharmacokinetic disposition parameters from the best fit model and the derived parameters of clearance in patients with renal impairment, simulation of colchicine plasma levels to target 0.5-3 ng/mL with colchicine oral solution was undertaken for various dose levels in different degrees of renal impairment.
With the standard colchicine 0.6 mg daily dose, plasma levels are expected to be therapeutic in patients with mild renal impairment (estimated glomerular filtration rate [eGFR] 60-89 mL/min/1.73 m). However, with this same 0.6 mg daily dose, patients with moderate renal impairment (eGFR 30-59 mL/min/1.73 m) and severe renal impairment (eGFR of 15-29 mL/min/1.73 m) would have excursions up to 10% and 36%, respectively, above the maximum tolerated level. Administering a lower dose such as 0.3 mg daily by splitting the conventional 0.6 mg tablet or by administering 0.6 mg once every-other-day (QOD) in moderate renal impairment would result in plasma colchicine levels in subtherapeutic range (< 0.5 ng/mL) for 20-70% of the dosing interval.
Analysis of pharmacokinetic model data confirms that the majority of patients with renal impairment taking colchicine solid dosage formulations will be above or below therapeutic levels, exposing them to potential side effects. However, more precise dosing with colchicine oral solution of 0.48 mg (4 mL) or 0.5 mg tablet available in certain countries for moderate renal impairment and 0.3 mg (2.5 mL) for severe renal impairment are associated with optimal levels and safer for patients with renal impairment. No dosage adjustment is needed for patients with mild renal impairment.
如果患者已有肾功能损害或存在药物相互作用，接受痛风发作标准预防剂量秋水仙碱的患者发生毒性反应的风险会增加。指南建议谨慎用药，剂量调整由临床医生酌情决定。
使用健康受试者中秋水仙碱口服溶液的药代动力学研究数据建立药代动力学模型。利用最佳拟合模型得出的药代动力学处置参数以及肾功能损害患者的清除率参数，针对不同程度肾功能损害的各种剂量水平，用秋水仙碱口服溶液模拟秋水仙碱血浆水平以达到0.5 - 3 ng/mL的目标值。
采用秋水仙碱每日标准剂量0.6 mg时，轻度肾功能损害患者（估计肾小球滤过率[eGFR] 60 - 89 mL/min/1.73 m²）的血浆水平预计处于治疗范围内。然而，同样是每日0.6 mg的剂量，中度肾功能损害患者（eGFR 30 - 59 mL/min/1.73 m²）和重度肾功能损害患者（eGFR 15 - 29 mL/min/1.73 m²）的血浆水平分别会比最大耐受水平高出10%和36%。在中度肾功能损害患者中，通过掰开常规的0.6 mg片剂服用较低剂量（如每日0.3 mg）或每隔一天服用0.6 mg，在给药间隔的20% - 70%时间内，秋水仙碱血浆水平会处于亚治疗范围（< 0.5 ng/mL）。
药代动力学模型数据分析证实，大多数服用秋水仙碱固体剂型的肾功能损害患者的血浆水平会高于或低于治疗水平，使他们面临潜在的副作用。然而，在某些国家，针对中度肾功能损害患者使用0.48 mg（4 mL）秋水仙碱口服溶液或0.5 mg片剂，针对重度肾功能损害患者使用0.3 mg（2.5 mL）秋水仙碱口服溶液进行更精确的给药，与最佳水平相关，对肾功能损害患者更安全。轻度肾功能损害患者无需调整剂量。
