目的:比较药物的药代动力学,和食物的影响,双氯芬酸钾作为口服溶液与速释片剂递送。
背景:双氯芬酸钾口服液是唯一一种非甾体类抗炎药,被批准用于急性治疗18岁或以上成人有或无先兆的偏头痛发作。它与碳酸氢钾作为缓冲剂一起配制以提高pH并因此增加双氯芬酸在口服给药后在胃的酸性环境中的水溶性。剂量是在给药前将50毫克双氯芬酸粉末钾溶解在1至2盎司(30至60毫升)水中,与食物摄入量相关的给药时间未指定-在达到主要终点的急性偏头痛发作受试者中的关键疗效和安全性试验就是这种情况。对于偏头痛发作的急性治疗,疼痛缓解的快速起效是可取的,并且可能与药物在体循环中的有效浓度的快速出现有关。口服给药的药物到达血液的速率受其制剂和胃中食物的存在的影响。本研究旨在研究双氯芬酸钾的2种制剂的药代动力学,速释片剂和口服溶液,并确定食物的效果。
方法:这是一个开放标签,随机化,单中心,在健康志愿者中进行交叉试验。使用计算机生成的列表以1:1:1:1的比例将受试者随机化。他们在4个序列中接受了单次50毫克剂量的双氯芬酸钾(ABCD,BADC,CDBA,和DCAB)在4个治疗期的每个期间。4种治疗方法是:A,口服溶液空腹;B,平板禁食;C,口服溶液喂养;和D,平板喂养。给药之间有≥7天的清除期。在给药后至多12小时采集用于药代动力学分析的血液样品并分析双氯芬酸浓度。药代动力学参数,包括峰值浓度(Cmax),时间到Cmax(tmax),从时间0到最后可测量浓度(AUCt)的浓度-时间曲线下面积(AUC),并使用非房室分析获得了到无穷大的外推(AUC∞)。对于两种制剂,在进食和禁食条件下在溶液和片剂之间以及在进食和禁食状态之间进行Cmax和AUC的比较评估。生物等效暴露定义为Cmax和AUC的几何平均比率及其90%置信区间在80.0-125.0%范围内。在整个试验期间监测不良事件(AE)。
结果:36名随机受试者中有61%是男性,91.7%是白种人,平均年龄(标准差[SD])为31.9(7.6)岁。33名(91.7%)受试者完成了所有4种治疗。
■在喂食条件下服用时,口服溶液导致中位tmax快约80%(0.17比1.25小时,P=.00015)和降低21%的Cmax(平均值±SD,ng/mL:506±305vs835±449,P=.00061)与片剂相比。两种制剂之间的AUC值相似。在禁食条件下服用时,口服溶液的中位tmax快50%(0.25比0.50小时,P=.00035)以实现高77%的Cmax(平均值±SD,ng/mL:与片剂相比,1620±538vs1160±452,P=.00032)。两种制剂之间的AUCt和AUC∞相似。
■在喂食条件下服用时,口服溶液导致相似的中位tmax(0.17vs0.25小时,P=.185)和降低64%的Cmax(平均值±SD,ng/mL:506±305vs1620±538,P<.00001)与空腹条件相比。相比之下,饲喂条件下的片剂导致统计学上显著延迟的中值tmax(1.25vs0.50,P=.00143)和降低Cmax~30%(平均值±SD,ng/mL:835±449vs1160±452,P=.00377)。两种制剂在进食和禁食条件之间的AUC值相似。12名受试者(33%)在研究期间经历了≥1次治疗引起的AE。所有不良事件均为轻度,未经治疗即可解决;均未导致研究中止。与溶液制剂相比,在接受片剂的受试者中报告了更多的治疗引起的AE(在禁食中20.0%对11.8%,在进食条件中17.1%对8.6%)。
结论:双氯芬酸钾口服液和片剂在进食和禁食条件下产生统计学上显著不同的Cmax和tmax,但类似的AUC。Fed条件显著降低了两种配方的Cmax,并大大延迟了片剂的tmax。但对溶液配方的tmax没有影响。这些数据提供了对更早和更大的暴露于双氯芬酸的重要性的见解,从溶液配方比片剂,这可能解释了该溶液在发作和持续疼痛减轻方面的优势,而不是在双盲中观察到的片剂配方,在欧洲进行的偏头痛患者的疗效/安全性研究。
OBJECTIVE: To compare the pharmacokinetics of, and food effect on, diclofenac potassium delivered as an oral solution vs an immediate-release tablet.
BACKGROUND: Diclofenac potassium for oral solution is the only nonsteroidal anti-inflammatory drug approved as monotherapy for the acute treatment of migraine attacks with or without aura in adults 18 years of age or older. It is formulated with potassium bicarbonate as a buffering agent to raise the pH and consequently increase the aqueous solubility of diclofenac in the acidic environment of the stomach following oral administration. The dosage is 50 mg of powdered diclofenac potassium dissolved in 1 to 2 ounces (30 to 60 mL) of water prior to administration, with dosing time in relation to food intake not specified - this was the case for the pivotal efficacy and safety trials in subjects with acute migraine attacks in which the primary endpoints were achieved. For acute treatment of migraine attacks, rapid onset of pain relief is desirable and is likely related to a rapid appearance of an effective concentration of the drug in the systemic circulation. The rate at which an orally administered drug reaches the blood is affected by both its formulation and the presence of food in the stomach. The present study was designed to investigate the pharmacokinetics of 2 formulations of diclofenac potassium, an immediate-release tablet and an oral solution, and to ascertain the effect of food.
METHODS: This was an open-label, randomized, single-center, crossover trial in healthy volunteers. Subjects were randomized using computer-generated list to 1:1:1:1 ratio. They received a single 50-mg dose of diclofenac potassium in 4 sequences (ABCD, BADC, CDBA, and DCAB) during each of the 4 treatment periods. The 4 treatments were: A, oral solution fasting; B, tablet fasting; C, oral solution fed; and D, tablet fed. There was a ≥7-day washout period between dosing. Blood samples for pharmacokinetic analysis were taken for up to 12 hours post-dose and analyzed for diclofenac concentrations. Pharmacokinetic parameters, including peak concentration (Cmax ), time to Cmax (tmax ), area under the concentration-time curve (AUC) from time 0 to last measurable concentration (AUCt ), and extrapolation to infinity (AUC∞ ) were obtained using non-compartmental analysis. Comparative assessments for Cmax and AUC were performed between the solution and tablet under fed and fasting conditions and between fed and fasting states for both formulations. Bioequivalent exposure was defined as the geometric mean ratio and its 90% confidence interval falling within 80.0-125.0% for Cmax and AUC. Adverse events (AEs) were monitored throughout the trial.
RESULTS: Sixty-one percent of the 36 randomized subjects were male, 91.7% were Caucasian, and the mean (standard deviation [SD]) age was 31.9 (7.6) years. Thirty-three (91.7%) subjects completed all 4 treatments.
UNASSIGNED: When taken under fed conditions, the oral solution resulted in an approximately 80% faster median tmax (0.17 vs 1.25 hours, P = .00015) and a 21% lower Cmax (mean ± SD, ng/mL: 506 ± 305 vs 835 ± 449, P = .00061) compared with the tablet. AUC values were similar between the 2 formulations. When taken under fasting conditions, the oral solution exhibited a 50% faster median tmax (0.25 vs 0.50 hours, P = .00035) to achieve a 77% higher Cmax (mean ± SD, ng/mL: 1620 ± 538 vs 1160 ± 452, P = .00032) compared with the tablet. AUCt and AUC∞ were similar between the 2 formulations.
UNASSIGNED: When taken under fed conditions, the oral solution resulted in a similar median tmax (0.17 vs 0.25 hours, P = .185) and 64% lower Cmax (mean ± SD, ng/mL: 506 ± 305 vs 1620 ± 538, P < .00001) compared with fasting conditions. In comparison, the tablets under fed conditions resulted in a statistically significantly delayed median tmax (1.25 vs 0.50, P = .00143) and ∼30% lower Cmax (mean ± SD, ng/mL: 835 ± 449 vs 1160 ± 452, P = .00377). AUC values were similar between fed and fasting conditions for both formulations. Twelve subjects (33%) experienced ≥1 treatment-emergent AE during the study. All AEs were mild and resolved without treatment; none resulted in study discontinuation. More treatment-emergent AEs were reported in subjects receiving the tablet compared with the solution formulation (20.0% vs 11.8 % in fasting and 17.1% vs 8.6% in fed conditions).
CONCLUSIONS: Diclofenac potassium oral solution and tablet formulations produced statistically significantly different Cmax and tmax but similar AUC under fed and fasting conditions. Fed conditions produced significantly lower Cmax for both formulations and profoundly delayed tmax for the tablet, but had no effect on tmax for the solution formulation. These data provide insights into the importance of an earlier and greater exposure to diclofenac arising from the solution formulation than the tablet, which may account for the superiority in the onset and sustained pain reduction for the solution than the tablet formulation observed in the double-blind, efficacy/safety study in migraine patients conducted in Europe.