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Optimizing circadian drug infusion schedules towards personalized cancer chronotherapy

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Hill, Roger, Innominato, Pasquale F., Lévi, Francis A. and Ballesta, Annabelle (2020) Optimizing circadian drug infusion schedules towards personalized cancer chronotherapy. PLoS Computational Biology, 16 (1). e1007218. doi:10.1371/journal.pcbi.1007218

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Official URL: https://doi.org/10.1371/journal.pcbi.1007218

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Abstract

Precision medicine requires accurate technologies for drug administration and proper systems pharmacology approaches for patient data analysis. Here, plasma pharmacokinetics (PK) data of the OPTILIV trial in which cancer patients received oxaliplatin, 5-fluorouracil and irinotecan via chronomodulated schedules delivered by an infusion pump into the hepatic artery were mathematically investigated. A pump-to-patient model was designed in order to accurately represent the drug solution dynamics from the pump to the patient blood. It was connected to semi-mechanistic PK models to analyse inter-patient variability in PK parameters. Large time delays of up to 1h41 between the actual pump start and the time of drug detection in patient blood was predicted by the model and confirmed by PK data. Sudden delivery spike in the patient artery due to glucose rinse after drug administration accounted for up to 10.7% of the total drug dose. New model-guided delivery profiles were designed to precisely lead to the drug exposure intended by clinicians. Next, the complete mathematical framework achieved a very good fit to individual time-concentration PK profiles and concluded that inter-subject differences in PK parameters was the lowest for irinotecan, intermediate for oxaliplatin and the largest for 5-fluorouracil. Clustering patients according to their PK parameter values revealed patient subgroups for each drug in which inter-patient variability was largely decreased compared to that in the total population. This study provides a complete mathematical framework to optimize drug infusion pumps and inform on inter-patient PK variability, a step towards precise and personalized cancer chronotherapy.

Item Type: Journal Article
Subjects: R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Medicine > Warwick Medical School > Biomedical Sciences
Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine
Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Drug delivery systems, Pharmacokinetics -- Mathematical models, Drug infusion pumps, Developmental pharmacology, Drug development -- Research, Circadian rhythms
Journal or Publication Title: PLoS Computational Biology
Publisher: Public Library of Science
ISSN: 1553-7358
Official Date: 26 January 2020
Dates:
DateEvent
26 January 2020Published
21 November 2019Accepted
Volume: 16
Number: 1
Article Number: e1007218
DOI: 10.1371/journal.pcbi.1007218
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
Open Access Version:
  • bioRxiv

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