PDF(Pubmed)
Abstract：
The traditional design of food-effect studies has a high patient burden for toxic drugs with long half-lives (e.g., anticancer agents). Microtracers could be used to assess food-effect in patients without influencing their ongoing treatment. The feasibility of a microtracer food-effect study during steady-state of the therapeutic drug was investigated in an in silico simulation study with alectinib as an example for a relative toxic drug with a long half-life. Microtracer pharmacokinetics were simulated based on a previously published population pharmacokinetic model and used for estimation of a model with and a model without food as a covariate on oral bioavailability of alectinib (assuming a 40% food-effect). Power was defined as the fraction of clinical trials where a significant (p < 0.01) food-effect was identified. The proposed study design of 10 patients on steady-state treatment, 10 blood samples collected within 24 h after administration and an assumed food-effect of 40% had a power of 99.9%. The mean estimated food-effect was 39.8% (80% confidence interval: 31.0%-48.6%). The feasibility of microtracer food-effect studies was demonstrated. The design of the microtracer food-effect study allowed estimation of the food-effect with minimal influence on therapeutic treatment and reducing patient burden compared to the traditional study design for toxic drugs with long half-lives.
摘要：
食物效应研究的传统设计对半衰期长的有毒药物有很高的患者负担(例如，抗癌剂）。微示踪剂可用于评估患者的食物效应，而不会影响他们正在进行的治疗。在计算机模拟研究中以alectinib作为具有长半衰期的相对毒性药物的示例，研究了在治疗药物稳态期间进行微示踪剂食物效应研究的可行性。基于先前发表的群体药代动力学模型模拟微示踪剂药代动力学，并用于评估具有食物的模型和不具有食物的模型作为阿来替尼口服生物利用度的协变量（假设40％的食物效应）。功效定义为临床试验的分数，其中确定了显着（p<0.01）的食物效应。对10例患者进行稳态治疗的拟议研究设计，给药后24小时内收集的10个血液样品和假定的40％的食物效应具有99.9％的功效。平均估计食物效应为39.8%(80%置信区间:31.0%-48.6%)。证明了微量示踪剂食品效应研究的可行性。与具有长半衰期的有毒药物的传统研究设计相比，微示踪剂食物效应研究的设计允许估计食物效应，对治疗性治疗和减少患者负担的影响最小。
