Kang Won-Ho, Lee Jae-Yeon, Chae Jung-Woo, Lee Kyeong-Ryoon, Baek In-Hwan, Kim Min-Soo, Back Hyun-Moon, Jung Sangkeun, Shaffer Craig, Savic Rada, Yun Hwi-Yeol
College of Pharmacy, Chungnam National University, Deajeon 34134, Korea.
Division of Convergence Technology New Drug Development Center, Osong Medical Innovation Foundation, Cheongju 28160, Korea.
Pharmaceuticals (Basel). 2021 Feb 3;14(2):114. doi: 10.3390/ph14020114.
Sample sizes for single-period clinical trials, including pharmacokinetic studies, are statistically determined by within-subject variability (WSV). However, it is difficult to determine WSV without replicate-designed clinical trial data, and statisticians typically estimate optimal sample sizes using total variability, not WSV. We have developed an efficient population-based method to predict WSV accurately with single-period clinical trial data and demonstrate method performance with eperisone. We simulated 1000 virtual pharmacokinetic clinical trial datasets based on single-period and dense sampling studies, with various study sizes and levels of WSV and interindividual variabilities (IIVs). The estimated residual variability (RV) resulting from population pharmacokinetic methods were compared with WSV values. In addition, 3 × 3 bioequivalence results of eperisone were used to evaluate method performance with a real clinical dataset. With WSV of 40% or less, regardless of IIV magnitude, RV was well approximated by WSV for sample sizes greater than 18 subjects. RV was underestimated at WSV of 50% or greater, even with datasets having low IIV and numerous subjects. Using the eperisone dataset, RV was 44% to 48%, close to the true value of 50%. In conclusion, the estimated RV accurately predicted WSV in single-period studies, validating this method for sample size estimation in clinical trials.
单周期临床试验（包括药代动力学研究）的样本量由受试者内变异性（WSV）通过统计学方法确定。然而，在没有重复设计的临床试验数据的情况下，很难确定WSV，统计学家通常使用总变异性而非WSV来估计最佳样本量。我们开发了一种基于群体的有效方法，利用单周期临床试验数据准确预测WSV，并以乙哌立松为例展示该方法的性能。我们基于单周期和密集采样研究模拟了1000个虚拟药代动力学临床试验数据集，具有不同的研究规模以及WSV和个体间变异性（IIV）水平。将群体药代动力学方法得出的估计残差变异性（RV）与WSV值进行比较。此外，使用乙哌立松的3×3生物等效性结果，通过真实临床数据集评估该方法的性能。当WSV为40%或更低时，无论IIV大小如何，对于样本量大于18名受试者的情况，RV能很好地由WSV近似。当WSV为50%或更高时，即使数据集的IIV较低且受试者众多，RV仍被低估。使用乙哌立松数据集时，RV为44%至48%，接近真实值50%。总之，在单周期研究中，估计的RV准确地预测了WSV，验证了该方法在临床试验样本量估计中的有效性。
