Palma-Aguirre Jose Antonio, Villalpando-Hernández Jorge, Novoa-Heckel Germán, Oliva Iván, Cariño Lizbeth, López-Bojórquez Ericka, Burke-Fraga Victoria, Namur Salvador, González-de la Parra Mario
Centro de Estudios Científicos y Clínicos Pharma, S.A. de C.V., Mexico City, Mexico.
Clin Ther. 2009 Feb;31(2):399-410. doi: 10.1016/j.clinthera.2009.02.002.
Naproxen sodium/paracetamol (acetaminophen) is a combination for the treatment of symptomatic pain and fever marketed both as a prescription and an over-the-counter product in Mexico.
The aim of these 2 studies was to compare the bioavailability and to determine the bioequivalence of 2 test formulations (an oral-tablet formulation containing the combination of naproxen sodium/paracetamol 275/300 mg and an oral-suspension formulation containing the combination of naproxen sodium/paracetamol 375/300 mg per 15 mL) with their corresponding listed reference-drug formulations in Mexico (a list issued by Mexican health authorities).
Two separate, single-dose, randomized, open-label, 2-period crossover, postmarketing studies were conducted. For each study, a different set of eligible subjects was selected comprising healthy Mexican adults of either sex, and subjects were randomly assigned to receive 1 test formulation of the combination of naproxen sodium/paracetamol followed by the corresponding reference-drug formulation, or vice versa, with a 1-week washout period between doses. After a 12-hour overnight fast, subjects received a single dose of naproxen sodium/paracetamol 275/300-mg tablet or naproxen sodium/paracetamol 375/300 mg per 15 mL suspension, depending on the study. For the analysis of pharmacokinetic parameters, including C(max), AUC from time 0 (baseline) to 48 hours (AUC(0-48)), and AUC from baseline to infinity (AUC(0-infinity)), blood samples were drawn at baseline and at 0.16, 0.33, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours after administration. The formulations were considered bioequivalent if the geometric mean ratios (test/reference) of the C(max) and AUC were within the predetermined range of 80% to 125%. Tolerability was determined by clinical assessment, monitoring vital signs, laboratory analysis results, and subject interviews regarding adverse events.
A total of 26 subjects (15 men, 11 women; mean [SD] age, 29 [8] years [range, 20-50 years]; weight, 63.1 [9] kg [range, 51.4-84.4 kg]; height, 164 [9] cm [range, 149-179 cm]; and body mass index [BMI], 23.53 [2.18] kg/m(2) [range, 18.54-26.82 kg/m(2)]) were enrolled to receive the suspension-dosage formulation; 13 subjects received the suspension-test formulation first. A total of 26 subjects (13 men, 13 women; mean [SD] age, 29 [8] years [range, 18-43 years]; weight, 64.3 [7.7] kg [range, 50.6-80.7 kg]; height, 165 [9] cm [range, 151-181 cm]; and BMI, 23.64 [2.43] kg/m(2) [range, 18.02-26.42 kg/m(2)]) were enrolled to receive the tablet-dosage formulation; 13 subjects received the tablet-test formulation first. No significant period or sequence effects were detected based on analysis of variance. For the suspension-dosage formulation, the 90% CIs for naproxen C(max), AUC(0-48), and AUC(0-infinity) were 93.06% to 104.00%, 93.50% to 98.44%, and 92.14% to 98.99%, respectively, and were 90.09% to 105.90%, 88.58% to 99.34%, and 91.43% to 101.55%, respectively, for paracetamol. For the tablet-dosage formulation, the 90% CIs for naproxen C(max), AUC(0-48), and AUC(0-infinity) were 102.83% to 117.15%, 96.59% to 104.26%, and 96.01% to 102.90%, respectively, and were 94.04% to 121.09%, 95.48% to 105.64%, and 96.64% to 105.42%, respectively, for paracetamol.
In these 2 small studies in healthy Mexican adult subjects, a single dose of naproxen sodium/paracetamol 275/300 mg of the test formulation of the tablet-dosage formulation or a single dose of naproxen sodium/paracetamol 375/300 mg per 15 mL of the test formulation of the suspension-dosage formulation was found to be bioequivalent to the corresponding reference formulations according to the regulatory definition of bioequivalence based on the rate and extent of absorption. All formulations were generally well tolerated.
萘普生钠/对乙酰氨基酚是一种用于治疗症状性疼痛和发热的复方制剂，在墨西哥作为处方药和非处方药销售。
这两项研究的目的是比较两种试验制剂（一种含萘普生钠/对乙酰氨基酚275/300 mg的口服片剂制剂和一种每15 mL含萘普生钠/对乙酰氨基酚375/300 mg的口服混悬液制剂）与墨西哥相应列出的参比制剂（墨西哥卫生当局发布的清单）的生物利用度，并确定生物等效性。
进行了两项独立的、单剂量、随机、开放标签、两周期交叉、上市后研究。每项研究均选择了一组不同的合格受试者，包括健康的成年墨西哥男女，受试者被随机分配接受1种萘普生钠/对乙酰氨基酚复方的试验制剂，随后接受相应的参比制剂，或反之，两次给药之间有1周的洗脱期。在禁食12小时过夜后，受试者根据研究情况接受单剂量的275/300 mg萘普生钠/对乙酰氨基酚片剂或每15 mL含375/300 mg萘普生钠/对乙酰氨基酚的混悬液。为了分析药代动力学参数，包括C(max)、从时间0（基线）到48小时的AUC(AUC(0-48))以及从基线到无穷大的AUC(AUC(0-∞))，在基线以及给药后0.16、0.33、0.5、0.75、1、1.25、1.5、2、2.5、3、4、6、8、12、24和48小时采集血样。如果C(max)和AUC的几何平均比值（试验/参比）在预定的80%至125%范围内，则认为制剂具有生物等效性。通过临床评估、监测生命体征、实验室分析结果以及受试者关于不良事件的访谈来确定耐受性。
共有26名受试者（15名男性，11名女性；平均[标准差]年龄，29[8]岁[范围，20 - 50岁]；体重，63.1[9]kg[范围，51.4 - 84.4 kg]；身高，164[9]cm[范围，149 - 179 cm]；体重指数[BMI]，23.53[2.18]kg/m²[范围，18.54 - 26.82 kg/m²]）入选接受混悬液剂型；13名受试者首先接受混悬液试验制剂。共有26名受试者（13名男性，13名女性；平均[标准差]年龄，29[8]岁[范围，18 - 43岁]；体重，64.3[7.7]kg[范围，50.6 - 80.7 kg]；身高，165[9]cm[范围，151 - 181 cm]；BMI，23.64[2.43]kg/m²[范围，18.02 - 26.42 kg/m²]）入选接受片剂剂型；13名受试者首先接受片剂试验制剂。基于方差分析未检测到显著的周期或序列效应。对于混悬液剂型，萘普生C(max)、AUC(0-48)和AUC(0-∞)的90%置信区间分别为93.06%至104.00%、93.50%至98.44%和92.14%至98.99%，对乙酰氨基酚的相应置信区间分别为90.09%至105.90%、88.58%至99.34%和91.43%至101.55%。对于片剂剂型，萘普生C(max)、AUC(0-48)和AUC(0-∞)的90%置信区间分别为102.83%至117.15%、96.59%至104.26%和96.01%至102.90%，对乙酰氨基酚的相应置信区间分别为94.04%至121.09%、95.48%至105.64%和96.64%至105.42%。
在这两项针对健康成年墨西哥受试者的小型研究中，根据基于吸收速率和程度的生物等效性监管定义，发现单剂量的片剂剂型试验制剂275/300 mg萘普生钠/对乙酰氨基酚或单剂量的混悬液剂型试验制剂每15 mL含375/300 mg萘普生钠/对乙酰氨基酚与相应的参比制剂具有生物等效性。所有制剂总体耐受性良好。
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