Comparative and quantitative assessment on statin efficacy and safety: insights into inter-statin and inter-individual variability via dose- and exposure-response relationships

<b>Introduction</b>: Statins are prescribed widely for cholesterol-lowering therapy, but it is known that their efficacy and safety profiles vary, despite the shared pharmacophore and pharmacological target. The immense body of related clinical and preclinical data offers a unique opportunity to explore the possible factors underlying inter-statin and inter-individual variabilities. <b>Area covered</b>: Clinical and preclinical data from various statins were compiled with regard to the efficacy (cholesterol-lowering effect) and safety (muscle toxicity). Based on the compiled data, dose- and exposure-response relationships were explored to obtain mechanistic and quantitative insights into the variations in the efficacy and safety profiles of statins. <b>Expert opinion</b>: Our analyses indicated that the inter-statin variability in the cholesterol-lowering effect may be mainly attributable to variations in potency of inhibition of the pharmacological target, rather than variations in drug exposure at the site of drug action. However, the drug exposure at the sites of drug action (i.e., the liver for efficacy and the muscle for safety) may contribute to the differences in the efficacy and safety observed in individual patients.

**引言**：他汀类药物（statins）被广泛应用于降胆固醇治疗，尽管这类药物拥有共同的药效团（pharmacophore）与药理靶点（pharmacological target），但其临床疗效与安全性特征仍存在显著差异。目前已积累了海量相关临床与临床前研究数据，为探究他汀类药物间以及个体间疗效与安全性变异性的潜在影响因素提供了独特契机。
**研究覆盖范围**：本研究收集了多种他汀类药物针对疗效（降胆固醇作用）与安全性（肌肉毒性（muscle toxicity））的临床及临床前数据。基于整合后的数据集，本研究对剂量-暴露量响应关系（dose- and exposure-response relationships）展开分析，以获取他汀类药物疗效与安全性特征差异的机制性与量化认知。
**专家观点**：本团队的分析结果表明，他汀类药物间降胆固醇作用的变异性，主要源于其对药理靶点的抑制效价差异，而非药物作用位点的暴露量变化。然而，药物作用位点（即发挥疗效的肝脏与引发安全风险的肌肉）的药物暴露量，或可解释不同患者间观察到的疗效与安全性差异。