Novartis Healthcare Pvt. Ltd., Hyderabad, India.
School of Mathematical Sciences, Queen Mary University of London, UK.
Stat Methods Med Res. 2020 Apr;29(4):1149-1166. doi: 10.1177/0962280219852582. Epub 2019 Jun 7.
Determination of the optimal dose is a critical objective in the drug developmental process. An optimal dose prevents over- and under-exposure to the treatment drug thereby facilitating superior patient experience and reduced costs to the healthcare system. In this paper, we present a method for model-based dose optimisation with simultaneous pharmacokinetic estimation of the model parameters. Multiple doses of the drug are considered and the objective is to maintain the blood concentration of the drug around a pre-decided target concentration. We consider an adaptive setting wherein the model parameters are estimated from the blood samples collected at D-optimal time points from all subjects enrolled so far in the trial. The estimated parameters are then used to determine the optimal dose regimen for the next cohort. This procedure continues until the condition of a pre-decided stopping rule is met. Simulation studies and sensitivity analysis are undertaken to validate the methodology. We also evaluate the performance of the methodology when carried out in a non-adaptive setting. A two-stage design is then presented which combines the advantages of the adaptive as well as the non-adaptive approach. We demonstrate that our methodology enables pharmacokinetic estimation and dose regimen optimisation simultaneously in an ethical and cost-effective manner protecting the subjects from the ill-effects of suboptimal dose regimens and economising the number of subjects required in the trial.
确定最佳剂量是药物开发过程中的一个关键目标。最佳剂量可防止治疗药物过度暴露和不足，从而为患者带来更好的体验，并降低医疗系统的成本。本文提出了一种基于模型的剂量优化方法，同时对模型参数进行药代动力学估计。考虑了多种剂量，目标是将药物的血药浓度维持在预定的目标浓度附近。我们考虑了一种自适应设置，其中从迄今为止所有入组患者的血液样本中以 D-最优时间点采集的样本中估计模型参数。然后，使用这些估计的参数来确定下一组的最佳剂量方案。此过程将继续进行，直到达到预定的停止规则条件。进行了模拟研究和敏感性分析以验证该方法。我们还评估了当在非自适应设置中执行时该方法的性能。然后提出了一种两阶段设计，它结合了自适应和非自适应方法的优点。我们证明，我们的方法能够以合乎道德和具有成本效益的方式同时进行药代动力学估计和剂量方案优化，保护患者免受不适当剂量方案的不良影响，并减少试验所需的受试者数量。
