The Impact of Drug Properties and Severity of Obesity on Renal Drug Clearance Through Glomerular Filtration and Active Tubular Secretion: A Systematic Analysis Using PBPK Modeling.

Abstract

Objective: 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_GF) and active tubular secretion (ATS/CL_ATS) and assesses the systematic accuracy of dosing based on allometric scaling with an exponent of 0.75 or flat dosing (exponent of 0).

Methods: A physiologically-based pharmacokinetic (PBPK) approach was used to simulate CL_GF and CL_ATS for 11,520 hypothetical drugs in typical subjects with body mass index (BMI) between 20 and 60. Correlations between changes in CL_GF and CL_ATS 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.

Results: CLr through GF and ATS increased with BMI, albeit to different extents, depending on drug properties. When BMI was below 30 kg/m² 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.

Conclusion: In individuals with a BMI above 30 kg/m², 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.