Universität zu Köln

Chen, Zhendong ORCID: 0000-0002-2035-635X (2025). Application of Population Pharmacokinetic Modeling to Assess Kidney Function and Renal Excretion of Substances in Humans. PhD thesis, Universität zu Köln.

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Abstract

Creatinine is a widely used endogenous biomarker for eGFR and was studied through a refined popPK model that estimated CGR and Vd using data from retrospective and prospective studies. A key advancement of this work is the development of a joint creatinine/iohexol model, which enabled more precise assessment of renal function by incorporating nCTS as a parameter to evaluate OCT2/MATE-mediated tubular secretion. This approach may improve differentiation between glomerular and tubular function in clinical settings, offering a more accurate method for renal function assessment compared to traditional creatinine-based equations. However, the accuracy of the joint model remains constrained by external factors, such as uncertainties in creatinine absorption and the small clinical sample size. The refined creatinine model was successfully applied to patients undergoing cardiac surgery to evaluate the degree of AKI and its association with potential contributing factors. However, the once-daily sampling schedule was not sufficient to generate substantial additional information on renal function using the model compared to raw concentration data. To enhance the utility of the model, more samples should be taken early after surgery, and it may be beneficial to administer iohexol before and shortly after surgery to assess AKI. Furthermore, the degree of AKI in these patients was limited in extent and duration, suggesting that more detailed monitoring may be relevant only in patients with risk factors. Vancomycin is primarily excreted renally, making accurate renal function assessment crucial for optimizing dosing. This dissertation developed a vancomycin popPK model, incorporating estimated CrCL as a predictor for systemic clearance and CSF protein concentration as a predictor for CSF penetration. Monte Carlo simulations were employed to evaluate the probability of achieving PK/PD targets while ensuring systemic exposure remained within the therapeutic range across various dosing regimens. Additionally, the model confirmed the feasibility of using distal port CSF sampling for TDM in patients with EVDs. However, the study was limited by sparse sampling, small sample size, and absence of measured GFR, which restricted exploration of the relationship between renal function and vancomycin clearance. Overall, this dissertation demonstrates the value of popPK modeling in improving renal function assessment and vancomycin dosing optimization, particularly through creatinine-based approaches. Future research should focus on refining these models with larger, more diverse datasets, and exploring simpler, more practical sampling strategies to improve accuracy and clinical applicability.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Chen, Zhendong zhendong.chen@uk-koeln.de orcid.org/0000-0002-2035-635X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-786050
Date:	2025
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Pharmakologie > Instítut für Pharmakologie
Subjects:	Natural sciences and mathematics Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Clinical pharmacology English Population pharmacokinetics English Glomerular filtration rate English Creatinine tubular secretion English Vancomycin English Iohexol English
Date of oral exam:	16 June 2025
Referee:	Name Academic Title Fuhr, Uwe Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/78605