A Physiological Approach to Pharmacokinetics in Chronic Kidney Disease

Abstract

The conventional approach to approximating the pharmacokinetics of drugs in patients with chronic kidney disease (CKD) only accounts for changes in the estimated glomerular filtration rate. However, CKD is a systemic and multifaceted disease that alters many body systems. Therefore, the objective of this exercise was to develop and evaluate a whole-body mechanistic approach to predicting pharmacokinetics in patients with CKD. Physiologically based pharmacokinetic models were developed in PK-Sim v8.0 (www.open-systems-pharmacology.org) to mechanistically represent the disposition of 7 compounds in healthy human adults. The 7 compounds selected were eliminated by glomerular filtration and active tubular secretion by the organic cation transport system to varying degrees. After a literature search, the healthy adult models were adapted to patients with CKD by numerically accounting for changes in glomerular filtration rate, kidney volume, renal perfusion, hematocrit, plasma protein concentrations, and gastrointestinal transit.Literature-informed interindividual variability was applied to the physiological parameters to facilitate a population approach.Model performance in CKD was evaluated against pharmacokinetic data from 8 clinical trials in the literature. Overall, integration of the CKD parameterization enabled exposure predictions that were within 1.5-fold error across all compounds and patients with varying stages of renal impairment. Notable improvement was observed over the conventional approach to scaling exposure, which failed in all but 1 scenario in patients with advanced CKD. Further research is required to qualify its use for first-in-CKD dose selection and clinical trial planning for a wider selection of renally eliminated compounds, including those subject to anion transport.

PBPK Simulation-Based Evaluation of Ganciclovir Crystalluria Risk Factors: Effect of Renal Impairment, Old Age, and Low Fluid Intake

“…adefovir, oseltamivir carboxylate [ 23 , 62 ]), with also some reports for substrates for OCT2/MATEs (e.g. metformin, atenolol, creatinine [ 26 , 46 , 63 ]) and OATP4C1/ P-gp (e.g. digoxin [ 14 ]).…”

Effect of CYP3A4 Inhibitors and Inducers on Pharmacokinetics and Pharmacodynamics of Saxagliptin and Active Metabolite M2 in Humans Using Physiological-Based Pharmacokinetic Combined DPP-4 Occupancy

“…It was reported that the C max and AUC 0-t of saxagliptin increased by less than 2-fold in patients with severe hepatic impairment but by more than 2-fold in patients with severe renal impairment, respectively ( Boulton, 2017 ). PK simulation in humans with hepatic or renal impairment is performed by modulating many physiological parameters based on healthy humans ( Malik et al, 2020 ). However, currently, this simulation model cannot simulate PK of patients with hepatic or renal impairment yet.…”

Physiologically based pharmacokinetic modelling and simulation to predict the plasma concentration profile of schaftoside after oral administration of total flavonoids of Desmodium styracifolium

“…The final virtual healthy individual models were replaced with individuals whose parameter sets were adapted for renal impairment meanwhile the parameters of drug were left unchanged. The whole-body anatomy and physiology in patients throughout the progressive stages of CKD such as kidney volume fraction, renal perfusion fraction, fraction unbound in plasma, gastric emptying time and small intestinal transit time were changed according to literatures ( Malik et al, 2020 ). Changes in the physiological parameters, resulting from decreased renal function, were listed in Table 2 .…”