Zhang Tan, Calvier Elisa A M, Krekels Elke H J, Knibbe Catherijne A J
Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Certara Inc, Princeton, NJ, USA.
Pharm Res. 2025 Jun 27. doi: 10.1007/s11095-025-03885-5.
The influence of obesity on renal drug clearance (CLr) remains difficult to predict. This study quantifies obesity-related alterations in CLr for drugs eliminated via glomerular filtration (GF/CL) and active tubular secretion (ATS/CL) and assesses the systematic accuracy of dosing based on allometric scaling with an exponent of 0.75 or flat dosing (exponent of 0).
A physiologically-based pharmacokinetic (PBPK) approach was used to simulate CL and CL for 11,520 hypothetical drugs in typical subjects with body mass index (BMI) between 20 and 60. Correlations between changes in CL and CL and subject or drug properties were investigated. Moreover, for each drug, CLr values scaled to individuals with obesity from CLr values in normal-weight individuals were compared to PBPK predictions of CLr. Systematic scaling accuracy was defined as the prediction error being less than ± 30% for all drugs.
CLr through GF and ATS increased with BMI, albeit to different extents, depending on drug properties. When BMI was below 30 kg/m and transporter activity remained unchanged, the CLr between subjects of normal weight and with overweight or obesity differed less than 30% and both scaling methods were systematically accurate. For individuals with higher BMI, drug properties need to be taken into account when defining scenarios of systematic scaling accuracy.
In individuals with a BMI above 30 kg/m, neither 0.75 allometric scaling nor no scaling (flat dosing) is systematically accurate for renally cleared drugs. Strategies are provided to define systematic scaling accuracy a priori, based on subject and drug properties.
肥胖对肾脏药物清除率（CLr）的影响仍难以预测。本研究量化了通过肾小球滤过（GF/CL）和肾小管主动分泌（ATS/CL）消除的药物中与肥胖相关的CLr变化，并评估基于指数为0.75的异速缩放或固定剂量（指数为0）给药的系统准确性。
采用基于生理的药代动力学（PBPK）方法，模拟体重指数（BMI）在20至60之间的典型受试者中11520种假设药物的CL和CL。研究了CL和CL变化与受试者或药物特性之间的相关性。此外，对于每种药物，将根据正常体重个体的CLr值按比例缩放至肥胖个体的CLr值与CLr的PBPK预测值进行比较。系统缩放准确性定义为所有药物的预测误差小于±30%。
通过GF和ATS的CLr随BMI增加，尽管程度不同，这取决于药物特性。当BMI低于30kg/m且转运体活性保持不变时，正常体重与超重或肥胖受试者之间的CLr差异小于30%，两种缩放方法在系统上都是准确的。对于BMI较高的个体，在定义系统缩放准确性的情况时需要考虑药物特性。
对于BMI高于30kg/m的个体，对于经肾脏清除的药物，0.75的异速缩放和不进行缩放（固定剂量）在系统上都不准确。提供了基于受试者和药物特性先验定义系统缩放准确性的策略。
