Author:
Scotcher Daniel,Galetin Aleksandra
Abstract
AbstractDosing guidance is often lacking for chronic kidney disease (CKD) due to exclusion of such patients from pivotal clinical trials. Physiologically based pharmacokinetic (PBPK) modelling supports model-informed dosing when clinical data are lacking, but application of these approaches to patients with impaired renal function is not yet at full maturity. In the current study, a ganciclovir PBPK model was developed for patients with normal renal function and extended to CKD population. CKD-related changes in tubular secretion were explored in the mechanistic kidney model and implemented either as proportional or non-proportional decline relative to GFR. Crystalluria risk was evaluated in different clinical settings (old age, severe CKD and low fluid intake) by simulating ganciclovir medullary collecting duct (MCD) concentrations. The ganciclovir PBPK model captured observed changes in systemic pharmacokinetic endpoints in mild-to-severe CKD; these trends were evident irrespective of assumed pathophysiological mechanism of altered active tubular secretion in the model. Minimal difference in simulated ganciclovir MCD concentrations was noted between young adult and geriatric populations with normal renal function and urine flow (1 mL/min), with lower concentrations predicted for severe CKD patients. High crystalluria risk was identified at reduced urine flow (0.1 mL/min) as simulated ganciclovir MCD concentrations exceeded its solubility (2.6–6 mg/mL), irrespective of underlying renal function. The analysis highlighted the importance of appropriate distribution of virtual subjects’ systems data in CKD populations. The ganciclovir PBPK model illustrates the ability of this translational tool to explore individual and combined effects of age, urine flow, and renal impairment on local drug renal exposure.
Graphical Abstract
Publisher
Springer Science and Business Media LLC
Reference67 articles.
1. GBD chronic kidney disease collaboration. global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395(10225):709–33. https://doi.org/10.1016/s0140-6736(20)30045-3.
2. Wu H, Huang J. Drug-induced nephrotoxicity: pathogenic mechanisms, biomarkers and prevention strategies. Curr Drug Metab. 2018;19(7):559–67. https://doi.org/10.2174/1389200218666171108154419.
3. Sommer J, Seeling A, Rupprecht H. Adverse drug events in patients with chronic kidney disease associated with multiple drug interactions and polypharmacy. Drugs Aging. 2020;37(5):359–72. https://doi.org/10.1007/s40266-020-00747-0.
4. European Medicines Agency. Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with decreased renal function (CHMP/EWP/225/02). London: Committee for Human Medicinal Products (CHMP); 2014.
5. US Food Drug Admin. Guidance for industry: pharmacokinetics in patients with impaired renal function—study design, data analysis, and impact on dosing and labeling (Revision 2). Silver Spring, MD. https://www.fda.gov/media/78573/download: US Food and Drug Administration; 2020. Accessed 26 Jun 2021.
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