Ballantyne C M, Pazzucconi F, Pintó X, Reckless J P, Stein E, McKenney J, Bortolini M, Chiang Y T
Baylor College of Medicine, Houston, Texas 77030, USA.
Clin Ther. 2001 Feb;23(2):177-92. doi: 10.1016/s0149-2918(01)80001-1.
At high doses, the pharmacokinetics of fluvastatin immediate-release (IR) are nonlinear, possibly due to saturation of hepatic uptake. Fluvastatin delivery to the liver in a slower but sustained fashion would be expected to avoid hepatic saturation without elevating systemic drug levels.
This pooled analysis compared the efficacy and tolerability of extended-release (XL) 80-mg and IR 40-mg formulations of fluvastatin in lowering low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels and raising high-density lipoprotein cholesterol (HDL-C) levels in patients with hypercholesterolemia.
Data were pooled from 3 double-blind, randomized, active-controlled, multicenter, parallel-group studies that compared changes in lipid and apolipoprotein levels with fluvastatin XL 80 mg at bedtime (HS) with changes in fluvastatin IR 40 mg HS or BID in patients aged > or =18 years with primary hypercholesterolemia (consistently elevated LDL-C level [> or =160 mg/dL] and plasma TG levels < or =400 mg/dL). The primary efficacy variable was percent change in LDL-C from baseline.
The pooled analysis provided an intent-to-treat efficacy study population of 1674 patients. At 4 weeks, fluvastatin XL 80 mg HS reduced LDL-C levels by a mean of 36.3% (median 38%), significantly greater than a mean reduction of 25.9% (median 27%) seen with fluvastatin IR 40 mg HS, and an incremental additional mean reduction in LDL-C of 10.4% (P < 0.001). At 4 and 24 weeks, fluvastatin XL 80 mg HS provided an LDL-C reduction equivalent to fluvastatin IR 40 mg BID (P < 0.001 for noninferiority). Significant, dose-related changes in HDL-C, LDL-C:HDL-C ratio, total cholesterol, TG, and apolipoprotein A-I and apolipoprotein B levels also occurred. Mean HDL-C level increased by 8.7% and median TG level decreased by 19% with fluvastatin XL 80 mg HS (P < 0.001 and P < 0.05 vs fluvastatin IR 40 mg HS, respectively). Maximum mean increases in HDL-C level (21%) and median decreases in TG level (31%) with fluvastatin XL 80 mg HS occurred in patients with type IIb dyslipidemia and the highest baseline TG. Adverse events were mild, with similar frequency in all treatment groups.
Once-daily administration of fluvastatin XL 80 mg provides enhanced efficacy with an additional 10.4% reduction in LDL-C levels compared with fluvastatin IR 40 mg HS, and superior increases in HDL-C levels, particularly in patients with elevated TG levels (P < 0.05 vs fluvastatin IR 40 mg HS). Fluvastatin XL 80 mg HS has a good tolerability profile and is effective as starting and maintenance lipid-lowering treatment in patients with type II hypercholesterolemia.
高剂量时，氟伐他汀速释（IR）制剂的药代动力学呈非线性，这可能是由于肝脏摄取饱和所致。预计以较慢但持续的方式将氟伐他汀输送到肝脏可避免肝脏饱和，同时不会提高全身药物水平。
这项汇总分析比较了氟伐他汀缓释（XL）80毫克制剂和IR 40毫克制剂在降低高胆固醇血症患者低密度脂蛋白胆固醇（LDL-C）和甘油三酯（TG）水平以及提高高密度脂蛋白胆固醇（HDL-C）水平方面的疗效和耐受性。
数据来自3项双盲、随机、活性对照、多中心、平行组研究，这些研究比较了年龄≥18岁的原发性高胆固醇血症患者（LDL-C水平持续升高[≥160毫克/分升]且血浆TG水平≤400毫克/分升）睡前服用80毫克氟伐他汀XL（HS）与服用40毫克氟伐他汀IR HS或每日两次（BID）时血脂和载脂蛋白水平的变化。主要疗效变量是LDL-C相对于基线的变化百分比。
汇总分析提供了一个意向性治疗疗效研究人群，共1674例患者。4周时，睡前服用80毫克氟伐他汀XL使LDL-C水平平均降低36.3%（中位数为38%），显著大于服用40毫克氟伐他汀IR HS时平均降低25.9%（中位数为27%），LDL-C额外平均降低10.4%（P<0.001）。在4周和24周时，睡前服用80毫克氟伐他汀XL降低LDL-C的效果与服用40毫克氟伐他汀IR BID相当（非劣效性P<0.001）。HDL-C、LDL-C:HDL-C比值、总胆固醇、TG以及载脂蛋白A-I和载脂蛋白B水平也发生了显著的剂量相关变化。睡前服用80毫克氟伐他汀XL时，HDL-C平均水平升高8.7%，TG中位数水平降低19%（分别与服用40毫克氟伐他汀IR HS相比，P<0.001和P<0.05）。在IIb型血脂异常且基线TG最高的患者中，睡前服用80毫克氟伐他汀XL使HDL-C水平最大平均升高21%，TG中位数水平最大降低31%。不良事件较轻，所有治疗组的发生频率相似。
与服用40毫克氟伐他汀IR HS相比，每日一次服用80毫克氟伐他汀XL疗效增强，LDL-C水平额外降低10.4%，HDL-C水平升高更显著，尤其是TG水平升高的患者（与服用40毫克氟伐他汀IR HS相比，P<0.05）。睡前服用80毫克氟伐他汀XL耐受性良好，是II型高胆固醇血症患者起始和维持降脂治疗的有效药物。
