Hammami Muhammad M, Yusuf Ahmed, Shire Faduma S, Hussein Rajaa, Al-Swayeh Reem
Clinical Studies and Empirical Ethics Department, King Faisal Specialist Hospital and Research Center, P O Box # 3354 (MBC 03), Riyadh, 11211, Saudi Arabia.
Alfaisal University College of Medicine, Riyadh, Saudi Arabia.
J Negat Results Biomed. 2017 May 23;16(1):10. doi: 10.1186/s12952-017-0075-2.
Medication effect is the sum of its drug, placebo, and drug*placebo interaction effects. It is conceivable that the interaction effect involves modulating drug bioavailability; it was previously observed that being aware of caffeine ingestion may prolong caffeine plasma half-life. This study was set to evaluate such concept using different drugs.
Balanced single-dose, two-period, two-group, cross-over design was used to compare the pharmacokinetics of oral cephalexin, ibuprofen, and paracetamol, each described by its name (overt) or as placebo (covert). Volunteers and study coordinators were deceived as to study aim. Drug concentrations were determined blindly by in-house, high performance liquid chromatography assays. Terminal-elimination half-life (t) (primary outcome), maximum concentration (C), C first time (T), terminal-elimination-rate constant (λ), area-under-the-concentration-time-curve, to last measured concentration (AUC), extrapolated to infinity (AUC), or to T of overt drug (AUC), and C/AUC were calculated blindly using standard non-compartmental method. Covert-vs-overt effect on drug pharmacokinetics was evaluated by analysis-of-variance (ANOVA, primary analysis), 90% confidence interval (CI) using the 80.00-125.00% bioequivalence range, and percentage of individual pharmacokinetic covert/overt ratios that are outside the +25% range.
Fifty, 30, and 50 healthy volunteers (18%, 10%, and 6% females, mean (SD) age 30.8 (6.2), 31.4 (6.6), and 31.2 (5.4) years) participated in 3 studies on cephalexin, ibuprofen, and paracetamol, respectively. Withdrawal rate was 4%, 0%, and 4%, respectively. Eighteen blood samples were obtained over 6, 10, and 14 h in each study period of the three drugs, respectively. ANOVA showed no significant difference in any pharmacokinetic parameter for any of the drugs. The 90% CIs for AUC, AUC, C, AUC, and C/AUC were within the bioequivalence range, except for ibuprofen C (76.66-98.99), ibuprofen C/AUC (77.19-98.39), and ibuprofen (45.32-91.62) and paracetamol (51.45-98.96) AUC. Out of the 126 individual covert/overt ratios, 2.0-16.7% were outside the +25% range for AUC, 2.0-4.2% for AUC, 25.0-44.9% for C, 67.3-76.7% for AUC, and 45.8-71.4% for T.
This study couldn't confirm that awareness of drug ingestion modulates its bioavailability. However, it demonstrates the trivial effect of blinding in bioequivalence studies and the extent of bio-variability that would be expected when comparing a drug product to itself.
ClinicalTrials.gov identifier: NCT01501747 (registered Dec 26, 2011).
药物效应是其药物、安慰剂及药物 - 安慰剂相互作用效应的总和。可以想象，相互作用效应涉及调节药物生物利用度；此前观察到，知晓摄入咖啡因可能会延长咖啡因的血浆半衰期。本研究旨在使用不同药物评估这一概念。
采用平衡单剂量、两期、两组交叉设计，比较口服头孢氨苄、布洛芬和对乙酰氨基酚的药代动力学，每种药物分别以其名称（公开）或作为安慰剂（隐蔽）呈现。志愿者和研究协调员对研究目的不知情。通过内部高效液相色谱法测定盲法测定药物浓度。采用标准非房室模型方法盲法计算终末消除半衰期（t）（主要结局）、最大浓度（C）、首次达到C的时间（T）、终末消除速率常数（λ）、至最后测定浓度的浓度 - 时间曲线下面积（AUC）、外推至无穷大的AUC（AUC）或公开药物至T的AUC（AUC）以及C/AUC。通过方差分析（ANOVA，主要分析）、使用80.00 - 125.00%生物等效性范围的90%置信区间（CI）以及超出±25%范围的个体药代动力学隐蔽/公开比值百分比，评估隐蔽与公开对药物药代动力学的影响。
分别有50名、30名和50名健康志愿者（女性分别占18%、10%和6%，平均（标准差）年龄30.8（6.2）岁、31.4（6.6）岁和31.2（5.4）岁）参与了关于头孢氨苄、布洛芬和对乙酰氨基酚的3项研究。退出率分别为4%、0%和4%。在三种药物的每个研究周期中，分别在6小时、10小时和14小时采集了18份血样。方差分析表明，任何一种药物的任何药代动力学参数均无显著差异。除布洛芬的C（76.66 - 98.99）、布洛芬的C/AUC（77.19 - 98.39）、布洛芬的AUC（45.32 - 91.62）和对乙酰氨基酚的AUC（51.45 - 98.96）外，AUC、AUC、C、AUC和C/AUC的90%置信区间均在生物等效性范围内。在126个个体隐蔽/公开比值中，AUC超出±25%范围的为2.0 - 16.7%，AUC为2.0 - 4.2%，C为25.0 - 44.9%，AUC为67.3 - 76.7%，T为45.8 - 71.4%。
本研究无法证实知晓药物摄入会调节其生物利用度。然而，它证明了在生物等效性研究中盲法的微小影响以及将一种药物产品与其自身进行比较时预期的生物变异性程度。
ClinicalTrials.gov标识符：NCT01501747（2011年12月26日注册）
