Endrenyi L, Zha J
Department of Pharmacology, Univeristy of Toronto, Ontario, Canada.
Clin Pharmacol Ther. 1994 Sep;56(3):331-8. doi: 10.1038/clpt.1994.144.
To compare efficiencies of randomized dose- and concentration-controlled trials (RDCT and RCCT) for estimating the parameters of concentration-effect relationships.
In 1991 Sanathanan and Peck (Controlled Clin Trials 1991;12:780-94) suggested that estimation by RDCT is biased and much less efficient than analysis by RCCT. Their conclusion was based on a pharmacodynamic model that characterizes the effect of theophylline in subjects with asthma, in which the response was related linearly to a limited range of concentrations and independent of concentration otherwise. Therefore it was intended to explore whether the conclusion of Sanathanan and Peck applied to other pharmacodynamic models.
The results of Sanathanan and Peck were confirmed for the restricted linear, baseline-plateau model: with large pharmacokinetic and no pharmacodynamic variability, RCCT was 3.1 times more efficient than RDCT. However, under the same conditions, the efficiency of RCCT exceeded that of RDCT only 1.5 and 1.2 times when response was related, without restrictions, to concentration and log concentration, respectively. Moreover, in the presence of even moderate pharmacodynamic variability, the ratio of RCCT/RDCT efficiencies did not exceed 1.30 and 1.08, respectively. The parameters estimated by RDCT with these two models were not biased. Finally, in the presence of interindividual variability of the median effective concentration (EC50), pharmacokinetic variability did not affect the observed variation of the parameters in the log-linear pharmacodynamic relationship.
RCCT generally estimates pharmacodynamic parameters with an efficiency that is not much higher than, or even similar to, those yielded by RDCT. Therefore statistical benefits often do not call for the application of RCCT. However, sometimes its use should be seriously considered, particularly for drugs having small therapeutic indexes or when the baseline and plateau of the response occur near the therapeutic region of concentrations.
比较随机剂量和浓度对照试验（RDCT和RCCT）在估计浓度-效应关系参数方面的效率。
1991年，Sanathanan和Peck（《对照临床试验》1991年；12：780 - 94）指出，RDCT估计存在偏差，且效率远低于RCCT分析。他们的结论基于一个描述茶碱对哮喘患者作用的药效学模型，其中反应在有限浓度范围内与浓度呈线性相关，其他情况下与浓度无关。因此，旨在探讨Sanathanan和Peck的结论是否适用于其他药效学模型。
对于受限线性、基线-平台模型，证实了Sanathanan和Peck的结果：在药代动力学大且无药效学变异性的情况下，RCCT的效率比RDCT高3.1倍。然而，在相同条件下，当反应分别无限制地与浓度和对数浓度相关时，RCCT的效率仅比RDCT高1.5倍和1.2倍。此外，即使存在中等程度的药效学变异性，RCCT与RDCT效率之比分别不超过1.30和1.08。用这两种模型由RDCT估计的参数无偏差。最后，在半数有效浓度（EC50）存在个体间变异性的情况下，药代动力学变异性不影响对数线性药效学关系中参数的观察变异。
RCCT通常估计药效学参数的效率并不比RDCT高很多，甚至与之相似。因此，统计学优势通常并不要求应用RCCT。然而，有时应认真考虑使用RCCT，特别是对于治疗指数小的药物或当反应的基线和平台出现在浓度治疗区域附近时。
