Schaefer H G, Heinig R, Ahr G, Adelmann H, Tetzloff W, Kuhlmann J
Institute of Clinical Pharmacology, Bayer AG, Wuppertal, Germany.
Eur J Clin Pharmacol. 1997;51(6):473-80. doi: 10.1007/s002280050233.
Nisoldipine, a calcium antagonist of the dihydropyridine class, has been used in the treatment of hypertension and angina pectoris. A new controlled-release dosage form (nisoldipine coat-core, NCC) has been developed to allow once daily dosing. In addition to a formal food interaction study as requested by regulatory authorities for controlled-release dosage forms, a subsequent study was conducted to determine the clinical relevance of the changes in nisoldipine plasma concentration vs time profiles seen in the food effect study.
After a placebo run-in phase of 6 days, 12 hypertensive patients started treatment with 20 mg NCC once daily (days 0-3, 5-6, 8-9). On days 4, 7 and 10 the NCC was substituted for 5, 10 and 20 mg nisoldipine solution, respectively, in order to obtain nisoldipine plasma concentration vs time profiles comparable to the ones resulting from the concomitant intake of food and NCC. Simultaneous measurements of blood pressure (BP) and nisoldipine concentration were performed on days 3, 4, 7 and 10.
The relationship between nisoldipine plasma concentrations and percentage reduction in BP [diastolic (DBP) and systolic (SBP), supine and standing] could be described by an Emax model. The mean maximum reduction (Emax) relative to baseline was about 36.4% and 37.7% (DBP, supine and standing) and 27.9% and 29.2% (SBP, supine and standing), respectively. The interindividual variability (% CV) in Emax was low, ranging from 17.6% to 28.8%. The mean nisoldipine plasma concentration corresponding to 50% of the maximum effect (EC50) ranged between 0.99 and 2.62 micrograms.l-1 with a pronounced interindividual variability (% CV) of 89.5-108.8%. Mean Cmax values after administration of the 30 and 40 mg NCC together with food were 4.5 and 7.5 micrograms.l-1, respectively. Based on the concentration-effect relationship established in the present study, the effect achieved with a concentration of 7.5 micrograms.l-1 will be about 77% of Emax for DBP and about 88% of Emax for SBP, respectively.
At the time of maximum plasma concentration the additional decrease in BP relative to baseline due to the food effect will be about 7-15% for DBP and 3-9% for SBP. After administration of the 10 mg solution with a mean Cmax of 8.7 micrograms.l-1, only headache and flush with mild severity have been reported as adverse events. These maximum concentrations are comparable to Cmax values seen after intake of 40 mg NCC with food. With regard to heart rate (HR) there were distinct differences between the two formulations: Following administration of 5, 10 and 20 mg nisoldipine solution, there were dose-dependent increases in HR by a maximum of 4, 12 and 16 beats.min-1, respectively, whereas the HR profile for the NCC was similar to that seen under placebo treatment.
尼索地平是一种二氢吡啶类钙拮抗剂，已用于治疗高血压和心绞痛。一种新的控释剂型（尼索地平包芯片，NCC）已被开发出来，可每日给药一次。除了按照监管机构对控释剂型的要求进行正式的食物相互作用研究外，还进行了一项后续研究，以确定在食物效应研究中观察到的尼索地平血浆浓度-时间曲线变化的临床相关性。
在6天的安慰剂导入期后，12名高血压患者开始每日一次服用20mg NCC（第0 - 3天、5 - 6天、8 - 9天）。在第4天、7天和10天，分别用5mg、10mg和20mg尼索地平溶液替代NCC，以获得与食物和NCC同时服用时产生的尼索地平血浆浓度-时间曲线相当的曲线。在第3天、4天、7天和10天同时测量血压（BP）和尼索地平浓度。
尼索地平血浆浓度与血压降低百分比[舒张压（DBP）和收缩压（SBP），仰卧位和站立位]之间的关系可用Emax模型描述。相对于基线的平均最大降低值（Emax）分别约为36.4%和37.7%（DBP，仰卧位和站立位）以及27.9%和29.2%（SBP，仰卧位和站立位）。Emax的个体间变异性（%CV）较低，范围为17.6%至28.8%。对应于最大效应50%的平均尼索地平血浆浓度（EC50）在0.99至2.62μg·L-1之间，个体间变异性（%CV）显著，为89.5 - 108.8%。与食物一起服用30mg和40mg NCC后的平均Cmax值分别为4.5μg·L-1和7.5μg·L-1。根据本研究建立的浓度-效应关系，浓度为7.5μg·L-1时所达到的效应分别约为DBP的Emax的77%和SBP的Emax的88%。
在血浆浓度达到最大值时，由于食物效应导致的相对于基线的额外血压降低对于DBP约为7 - 15%，对于SBP约为3 - 9%。服用平均Cmax为8.7μg·L-1的10mg溶液后，仅报告有轻度的头痛和面部潮红等不良事件。这些最大浓度与与食物一起服用40mg NCC后观察到的Cmax值相当。关于心率（HR），两种制剂之间存在明显差异：服用5mg、10mg和20mg尼索地平溶液后，HR分别最多有剂量依赖性增加4次、12次和16次·min-1，而NCC的HR曲线与安慰剂治疗下观察到的相似。
