Personalized Chronomodulated 5‐Fluorouracil Treatment: A Physiologically‐Based Pharmacokinetic Precision Dosing Approach for Optimizing Cancer Therapy
Clinical Pharmacology & Therapeutics, vol. 115, pp. 1282–1292
Abstract
The discovery of circadian clock genes greatly amplified the study of diurnal variations impacting cancer therapy, transforming it into a rapidly growing field of research. Especially, use of chronomodulated treatment with 5‐fluorouracil (5‐FU) has gained significance. Studies indicate high interindividual variability (IIV) in diurnal variations in dihydropyrimidine dehydrogenase (DPD) activity – a key enzyme for 5‐FU metabolism. However, the influence of individual DPD chronotypes on chronomodulated therapy remains unclear and warrants further investigation. To optimize precision dosing of chronomodulated 5‐FU, this study aims to: (i) build physiologically‐based pharmacokinetic (PBPK) models for 5‐FU, uracil, and their metabolites, (ii) assess the impact of diurnal variation on DPD activity, (iii) estimate individual DPD chronotypes, and (iv) personalize chronomodulated 5‐FU infusion rates based on a patient's DPD chronotype. Whole‐body PBPK models were developed with PK‐Sim(R) and MoBi(R). Sinusoidal functions were used to incorporate variations in enzyme activity and chronomodulated infusion rates as well as to estimate individual DPD chronotypes from DPYD mRNA expression or DPD enzymatic activity. Four whole‐body PBPK models for 5‐FU, uracil, and their metabolites were established utilizing data from 41 5‐FU and 10 publicly available uracil studies. IIV in DPD chronotypes was assessed and personalized chronomodulated administrations were developed to achieve (i) comparable 5‐FU peak plasma concentrations, (ii) comparable 5‐FU exposure, and (iii) constant 5‐FU plasma levels via “noise cancellation” chronomodulated infusion. The developed PBPK models capture the extent of diurnal variations in DPD activity and can help investigate individualized chronomodulated 5‐FU therapy through testing alternative personalized dosing strategies.
Authors 8
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Affiliation as printed
Clinical Pharmacy Saarland University Saarbruecken Germany
Clinical Pharmacy, Saarland University, Saarbruecken, Germany
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Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology · Saarland University
Affiliation as printed
Clinical Pharmacy Saarland University Saarbruecken Germany
Dr. Margarete Fischer‐Bosch‐Institut of Clinical Pharmacology Stuttgart Germany
Clinical Pharmacy, Saarland University, Saarbruecken, Germany
Dr. Margarete Fischer-Bosch-Institut of Clinical Pharmacology, Stuttgart, Germany
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Affiliation as printed
Clinical Pharmacy Saarland University Saarbruecken Germany
Clinical Pharmacy, Saarland University, Saarbruecken, Germany
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Affiliation as printed
Division of Biomedical Sciences, Warwick Medical School University of Warwick Coventry UK
Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, UK
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Jesse Joachim Swen Aachen Department of Clinical Pharmacy & Toxicology Leiden University Medical Center RC Leiden The Netherlands
Leiden University Medical Center
Affiliation as printed
Department of Clinical Pharmacy & Toxicology Leiden University Medical Center RC Leiden The Netherlands
Department of Clinical Pharmacy & Toxicology Leiden University Medical Center RC Leiden The Netherlands
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Henk‐Jan Guchelaar Aachen Department of Clinical Pharmacy & Toxicology Leiden University Medical Center RC Leiden The Netherlands
Leiden University Medical Center
Affiliation as printed
Department of Clinical Pharmacy & Toxicology Leiden University Medical Center RC Leiden The Netherlands
Department of Clinical Pharmacy & Toxicology Leiden University Medical Center RC Leiden The Netherlands
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Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology · University of Tübingen
Affiliation as printed
Cluster of excellence iFIT (EXC2180) “Image‐Guided and Functionally Instructed Tumor Therapies” University Tuebingen Tuebingen Germany
Departments of Clinical Pharmacology, and of Biochemistry and Pharmacy University Tuebingen Tuebingen Germany
Dr. Margarete Fischer‐Bosch‐Institut of Clinical Pharmacology Stuttgart Germany
Cluster of excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies", University Tuebingen, Tuebingen, Germany
Departments of Clinical Pharmacology, and of Biochemistry and Pharmacy, University Tuebingen, Tuebingen, Germany
Dr. Margarete Fischer-Bosch-Institut of Clinical Pharmacology, Stuttgart, Germany
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Thorsten Lehr corresponding
Affiliation as printed
Clinical Pharmacy Saarland University Saarbruecken Germany
Clinical Pharmacy, Saarland University, Saarbruecken, Germany
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