Clinical Pharmacology of Pemafibrate Extended-release Formulation in Patients with Hypertriglyceridemia-A Phase 2, Multicenter, Active-controlled, Randomized, Single-blind, Crossover study.

IF 3 2区医学 Q2 PERIPHERAL VASCULAR DISEASE

Journal of atherosclerosis and thrombosis Pub Date : 2024-09-26 DOI:10.5551/jat.65001

Shizuya Yamashita, Eiichi Araki, Hidenori Arai, Koutaro Yokote, Ryohei Tanigawa, Ayumi Saito, Hideki Suganami, Sara Minamikawa, Shun Ishibashi

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Abstract

Aims: Efficacy, safety, and pharmacokinetics of the selective PPARα modulator pemafibrate as once-daily extended-release (XR) tablets were compared with those of twice-daily immediate-release (IR) tablets in patients with hypertriglyceridemia.

Methods: A multicenter, randomized, single-blind, active-controlled crossover, phase 2 clinical pharmacology study was performed in patients with hypertriglyceridemia. Patients were randomly assigned to IR 0.2 mg/day, XR 0.4 mg/day, or XR 0.8 mg/day before/after meals (fasted/fed) and treated for a total of eight weeks. The primary endpoint was percentage change in fasting serum triglycerides (TG).

Results: Of 63 randomized patients, 60 received the study drug. Patients were 78.3% male, mean age (±SD) 57.5±9.8 years, BMI 25.5±3.7 kg/m², and fasting TG 221.3±68.1 mg/dL. Fasting serum TG decreased significantly from baseline in all groups (LS mean [95% CI];-43.6 [-47.7, -39.5] % for IR 0.2 mg/day, -41.1 [-45.1, -37.0] % for XR 0.4mg/day, -39.7 [-43.8, -35.6] % for XR 0.8 mg/day), indicating that XR 0.4 and XR 0.8 mg/day were not inferior to IR 0.2 mg/day. TG-lowering effects tended to be stronger for fed than fasted administration. MRT_ss, t_max, and t_1/2 were longer for XR than for IR. Adverse events showed no major inter-group differences: 12.5% (5/40 patients) for IR 0.2, 17.5% (7/40) for XR 0.4, and 20.0% (8/40) for XR 0.8 mg/day.

Conclusions: In patients with hypertriglyceridemia, XR substantially lowered TG at all doses, with maximum effectiveness at 0.4 mg/day, the dose approved in Japan, to a level comparable to IR 0.2 mg/day. There were no safety concerns up to 0.8 mg/day.

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高甘油三酯血症患者服用培马贝特缓释制剂的临床药理学--一项 2 期、多中心、主动对照、随机、单盲、交叉研究。

目的：比较高甘油三酯血症患者服用选择性 PPARα 调节剂培马贝特（每日一次的缓释片，XR）与每日两次的速释片（IR）的疗效、安全性和药代动力学：在高甘油三酯血症患者中开展了一项多中心、随机、单盲、主动对照交叉2期临床药理研究。患者被随机分配到 IR 0.2 毫克/天、XR 0.4 毫克/天或 XR 0.8 毫克/天，餐前/餐后（空腹/进食），共治疗 8 周。主要终点是空腹血清甘油三酯（TG）的百分比变化：在 63 名随机患者中，60 人接受了研究药物治疗。患者中78.3%为男性，平均年龄（±SD）为57.5±9.8岁，体重指数（BMI）为25.5±3.7 kg/m2，空腹甘油三酯（TG）为221.3±68.1 mg/dL。所有组的空腹血清 TG 均较基线显著下降（LS 平均值[95% CI]；IR 0.2 mg/ 天为 -43.6 [-47.7, -39.5] %，XR 0.4 mg/ 天为 -41.1 [-45.1, -37.0] %，XR 0.8 mg/ 天为 -39.7 [-43.8, -35.6]%），表明 XR 0.4 和 XR 0.8 mg/ 天并不比 IR 0.2 mg/ 天差。与空腹给药相比，进食给药的降 TG 作用更强。XR的MRTss、tmax和t1/2均长于IR。不良反应在组间无明显差异：IR 0.2的不良反应发生率为12.5%（5/40），XR 0.4的不良反应发生率为17.5%（7/40），XR 0.8 mg/天的不良反应发生率为20.0%（8/40）：在高甘油三酯血症患者中，XR 在所有剂量下都能显著降低总甘油三酯，在 0.4 毫克/天（日本批准的剂量）时疗效最佳，与 IR 0.2 毫克/天的疗效相当。在0.8毫克/天的剂量范围内没有安全性问题。

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