Perrottet Nancy, Brunner-Ferber Françoise, Grouzmann Eric, Spertini François, Biollaz Jérôme, Buclin Thierry, Widmer Nicolas
Service of Pharmacy, Lausanne University Hospital, Lausanne, Switzerland.
Brunner Naga, Health Science Consulting, Pfäffikon-ZH, Switzerland.
Trials. 2016 Jul 16;17(1):321. doi: 10.1186/s13063-016-1463-5.
During clinical trials, researchers rarely question nominal doses specified on labels of investigational products, overlooking the potential for inaccuracies that may result when calculating pharmacokinetic and pharmacodynamic parameters. This study evaluated the disparity between nominal doses and the doses actually administered in two Phase I trials of a biosimilar drug.
In Trial A, 12 healthy volunteers received various doses of an interferon β-1a biosimilar via either subcutaneous or intravenous injection, prepared by partially emptying 0.53 ml syringes supplied by the manufacturer. In Trial B, 12 volunteers received three different formulations of the drug via intravenous injection (biosimilar with and without albumin and a comparator), followed by multiple subcutaneous injections. In both trials, the dose administered was calculated as D = C × V - losses, where C is the drug concentration assessed using ELISA, V is the volume administered calculated using syringe weighing and losses are deduced from in-vitro experiments. Interferon binding to added albumin and infusion lines was evaluated using a (125)I-interferon tracer with gel-filtration chromatography.
In Trial A, measured concentrations were close to the nominal strength indicated by the manufacturer (median bias: -6 %), whereas in Trial B they differed significantly for all three formulations (median biases: +67 %, +73 % and +31 % for the biosimilar with albumin, the biosimilar without albumin and the comparator, respectively). In Trial A, the doses actually administered showed large variability and biases, especially at the lowest doses. Indeed, actually injected volumes differed by as much as 74 % from theoretical volumes - a phenomenon mainly attributed to unnoticed fluid re-aspiration through the syringe needle. This was corrected in Trial B. Interferon was not significantly adsorbed on the infusion lines used for intravenous administration. Its binding to albumin was slow, reaching 50 % after a 16 h incubation.
These examples illustrate the importance of assessing the actual doses administered in clinical trials, to ensure accuracy in the determination of clearance, distribution volume, bioavailability and dose-response relationships.
Clinicaltrials.gov NCT02515695 (Trial A) and NCT02517788 (Trial B). Registered on 24 July and 5 August 2015, respectively.
在临床试验期间，研究人员很少质疑研究产品标签上规定的标称剂量，忽视了计算药代动力学和药效学参数时可能产生的不准确情况。本研究评估了生物类似药两项Ⅰ期试验中标称剂量与实际给药剂量之间的差异。
在试验A中，12名健康志愿者通过皮下或静脉注射接受了不同剂量的干扰素β-1a生物类似药，药物通过排空制造商提供的0.53 ml注射器部分制备。在试验B中，12名志愿者通过静脉注射接受了该药物的三种不同制剂（含白蛋白和不含白蛋白的生物类似药以及一种对照药），随后进行多次皮下注射。在两项试验中，给药剂量的计算方式为D = C×V - 损失量，其中C是使用酶联免疫吸附测定法（ELISA）评估的药物浓度，V是使用注射器称重法计算的给药体积，损失量则根据体外实验推导得出。使用（125）I-干扰素示踪剂和凝胶过滤色谱法评估干扰素与添加的白蛋白和输液管路的结合情况。
在试验A中，测得的浓度接近制造商标明的标称浓度（中位偏差：-6%），而在试验B中，所有三种制剂的浓度均存在显著差异（含白蛋白的生物类似药、不含白蛋白的生物类似药和对照药的中位偏差分别为+67%、+73%和+31%）。在试验A中，实际给药剂量显示出很大的变异性和偏差，尤其是在最低剂量时。实际上，实际注射体积与理论体积相差高达74%——这种现象主要归因于通过注射器针头未被注意到的液体回吸。试验B中对此进行了纠正。干扰素在用于静脉给药的输液管路上没有明显吸附。其与白蛋白的结合较慢，孵育16小时后达到50%。
这些例子说明了评估临床试验中实际给药剂量的重要性，以确保清除率、分布容积、生物利用度和剂量反应关系测定的准确性。
Clinicaltrials.gov NCT02515695（试验A）和NCT02517788（试验B）。分别于2015年7月24日和8月5日注册。
