The impact of drug properties and severity of obesity on renal clearance through glomerular filtration and active tubular secretion
Tan Zhang (1), Elisa A.M. Calvier (2), Elke H.J. Krekels (1,3)*, Catherijne A.J. Knibbe (1,4)*
(1) Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (2) Pharmacokinetics-Dynamics and Metabolism, Translational Medicine and Early Development, Sanofi R&D, Montpellier, France (3) Certara Inc, Princeton, NJ, USA (4) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands *Both authors contributed equally
Objectives:
Obesity is a global health concern, but its influence on renal clearance (CLr) of drugs remains unclear. Obesity may lead to a higher glomerular filtration (GF) rate, but studies show that while CLr is enhanced in obese subjects for some drugs, it remains unaltered for many others [1]. This may stem from alterations in active tubular secretion (ATS) counteracting the impact of GF alterations, however, how ATS changes with obesity remains unknown. Moreover, predictors for selecting appropriate dose scaling methods for obese subjects are lacking. In this study, we use a PBPK approach to study obesity-related changes in CLr for drugs eliminated via GF and ATS and explore the impact of hypothetical obesity-related changes in ATS on total CLr under various scenarios. Furthermore, the systematic accuracy of commonly used scaling methods in predicting CLr is assessed.
Methods:
R (version 4.0.3) was used to perform simulations using a PBPK-based workflow [2]. In this workflow, 11520 hypothetical drugs were generated with all possible combinations of the following realistic ranges in drug properties in normal-weight individuals: 1) fraction unbound (fu, 1-100%), 2) blood-to-plasma partition coefficient (kp, 0.35-40), and 3) transporter-mediated intrinsic ATS clearance (CLint_ATS, 2-500 ul-1min-1mg protein-1). All drugs were assumed to exclusively bind to either human serum albumin (HSA) or alpha1-acid glycoprotein. For ATS, varying hypothetical degrees of overweight- and obesity-induced changes were investigated, ranging from a reduction of down to 20% to an increase of up to 150% compared to normal activity. CLr for all drugs was predicted for a normal-weight subject and five overweight and obese subjects (BMI 25-60 kg/m2) using previously reported changes in subject-specific parameter values [3] and the hypothetical changes in ATS. The obesity-related changes in GF and ATS were determined and their correlations with subject and drug properties were investigated. Besides this, the prediction error (PE) between the PBPK-based CLr predictions for subjects with obesity and the CLr predictions by allometric scaling with an exponent of 0.75 (AS0.75) and flat dosing (exponent of zero), was obtained to assess their accuracy. Systematic accuracy was defined as PE values of all hypothetical drugs being within ±30%.
Results:
CLr through both GF and ATS increases with BMI, with approximately a 75% increase in CLr as BMI increases from 20 to 60 kg/m2. In addition to BMI, CLr through GF is largely dependent on fu. For drugs mainly cleared by GF (i.e., CLint_ATS = 5 ul-1min-1mg protein-1), CLr increases between 1.70 and 1.49 fold when BMI increases from 25 to 60 kg/m2 for drugs with a fu of 5% or 95% respectively. For drugs cleared through ATS, CLr is dependent on several variables, such as fu, CLint_ATS, and changes in transporter activity. When BMI is below 30 kg/m² and transporter activity remains unchanged or decreases down to 50%, the CLr in obese subjects compared to normal-weight subjects changes with less than ±30%, regardless of drug properties. When transporter activity decreases by over 50%, the CLr in obese subjects is reduced by over 30% in comparison to those with normal weight, indicating a decreased CLr through ATS. At higher BMIs, the impact of potential changes in ATS increases for drugs with decreasing fu and CLint_ATS.
With respect to the application of scaling methods, when subjects have a BMI below 30 kg/m2 and an unaltered ATS activity, both AS0.75 and flat dosing are systematically accurate. At BMI >30 kg/m2, changes in CLr become too variable to derive generalizable scaling rules. In scenarios of an increased transporter activity of up to 150%, AS0.75 is accurate, but only for HSA-bound drugs. When transporter activity is reduced to 50%, flat dosing becomes the only accurate dosing method.
Conclusions:
In this PBPK-based study, we found that when BMI is below 30 kg/m² and transporter activity remains unchanged or decreases down to 50%, flat dosing would be an appropriate dosing method. When transporter activity decreases by over 50%, CLr through ATS decreases, potentially offsetting the rise in CLr through GFR, resulting in unchanged total CLr. It is not possible to define one appropriate scaling method for all drugs. It may be possible to define appropriate methods for a limited subset of scenarios, in all other cases additional information on fu and CLint_ATS is required.
References:
[1] Zhang T et al. Expert Opin Drug Metab Toxicol. 2022;18(10):657-674.
[2] Calvier EAM, et al. Clin Pharmacokinet. 2017; 273-285.
[3] Berton, M, et al. Clin Pharmacokinet. 2022; 1251-1270.