Pai Manjunath P, Crass Ryan L
Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Rm 2568, 428 Church St., Ann Arbor, MI 48109, USA.
Ann Arbor Pharmacometrics Group, Ann Arbor, MI 48108, USA.
Antibiotics (Basel). 2021 Nov 9;10(11):1368. doi: 10.3390/antibiotics10111368.
Antibiotic efficacy determination in clinical trials often relies on non-inferiority designs because they afford smaller study sample sizes. These efficacy studies tend to exclude patients within specific populations or include too few patients to discern potential differences in their clinical outcomes. As a result, dosing guidance in patients with abnormal liver and kidney function, age across the lifespan, and other specific populations relies on drug exposure-matching. The underlying assumption for exposure-matching is that the disease course and the response to the antibiotic are similar in patients with and without the specific condition. While this may not be the case, clinical efficacy studies are underpowered to ensure this is true. The current paper provides an integrative review of the current approach to dose selection in specific populations. We review existing clinical trial endpoints that could be measured on a more continuous rather than a discrete scale to better inform exposure-response relationships. The inclusion of newer systemic biomarkers of efficacy can help overcome the current limitations. We use a modeling and simulation exercise to illustrate how an efficacy biomarker can inform dose selection better. Studies that inform response-matching rather than exposure-matching only are needed to improve dose selection in specific populations.
临床试验中的抗生素疗效测定通常依赖于非劣效性设计，因为它们所需的研究样本量较小。这些疗效研究往往会排除特定人群中的患者，或者纳入的患者过少，无法辨别其临床结局的潜在差异。因此，针对肝肾功能异常患者、不同年龄段患者以及其他特定人群的给药指导依赖于药物暴露匹配。暴露匹配的潜在假设是，患有和未患有特定疾病的患者的病程和对抗生素的反应相似。虽然情况可能并非如此，但临床疗效研究的力度不足以确保这一点。本文对特定人群中当前的剂量选择方法进行了综合综述。我们回顾了现有的临床试验终点，这些终点可以在更连续而非离散的尺度上进行测量，以便更好地了解暴露-反应关系。纳入更新的全身疗效生物标志物有助于克服当前的局限性。我们通过建模和模拟演练来说明疗效生物标志物如何能更好地为剂量选择提供依据。需要开展仅针对反应匹配而非暴露匹配的研究，以改善特定人群的剂量选择。
