Department of Pharmacy, Uppsala University, Uppsala, Sweden.
Department of Internal Medicine, Amsterdam UMC, Location VU University, Amsterdam, The Netherlands.
Clin Transl Sci. 2023 Jan;16(1):73-84. doi: 10.1111/cts.13423. Epub 2022 Oct 18.
Blood pressure measurements form a critical component of adverse event monitoring for tyrosine kinase inhibitors, but might also serve as a biomarker for dose titrations. This study explored the impact of various sources of within-individual variation on blood pressure readings to improve measurement practices and evaluated the utility for individual- and population-level dose selection. A pharmacokinetic-pharmacodynamic modeling framework was created to describe circadian blood pressure changes, inter- and intra-day variability, changes from dipper to non-dipper profiles, and the relationship between drug exposure and blood pressure changes over time. The framework was used to quantitatively evaluate the influence of physiological and pharmacological aspects on blood pressure measurements, as well as to compare measurement techniques, including office-based, home-based, and ambulatory 24-h blood pressure readings. Circadian changes, as well as random intra-day and inter-day variability, were found to be the largest sources of within-individual variation in blood pressure. Office-based and ambulatory 24-h measurements gave rise to potential bias (>5 mmHg), which was mitigated by model-based estimations. Our findings suggest that 5-8 consecutive, home-based, measurements taken at a consistent time around noon, or alternatively within a limited time frame (e.g., 8.00 a.m. to 12.00 p.m. or 12.00 p.m. to 5.00 p.m.), will give rise to the most consistent blood pressure estimates. Blood pressure measurements likely do not represent a sufficiently accurate method for individual-level dose selection, but may be valuable for population-level dose identification. A user-friendly tool has been made available to allow for interactive blood pressure simulations and estimations for the investigated scenarios.
血压测量是酪氨酸激酶抑制剂不良事件监测的关键组成部分，但也可以作为剂量调整的生物标志物。本研究探讨了个体内变异的各种来源对血压读数的影响，以改进测量实践，并评估了个体和人群水平剂量选择的实用性。创建了一个药代动力学-药效学建模框架来描述血压的昼夜变化、日内和日间变异性、从杓型到非杓型的变化，以及药物暴露与随时间变化的血压变化之间的关系。该框架用于定量评估生理和药理方面对血压测量的影响，并比较测量技术，包括基于诊室的、基于家庭的和动态 24 小时血压读数。昼夜变化以及随机日内和日间变异性是血压个体内变异的最大来源。基于诊室和动态 24 小时的测量会产生潜在的偏差（>5mmHg），通过基于模型的估计可以减轻这种偏差。我们的研究结果表明，在中午左右的一致时间点进行 5-8 次连续的家庭测量，或者在有限的时间范围内（例如，上午 8.00 至下午 12.00 或下午 12.00 至下午 5.00），将产生最一致的血压估计值。血压测量可能不是个体水平剂量选择的足够准确方法，但可能对人群水平剂量识别有价值。我们提供了一个用户友好的工具，允许对所研究的场景进行交互式血压模拟和估计。
