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 ISSN 1553-7358.
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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 Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Science, Engineering and Medicine > 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: | Date Event 26 January 2020 Published 21 November 2019 Accepted |
| 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 (Creative Commons open licence) |
| Date of first compliant deposit: | 19 April 2021 |
| Date of first compliant Open Access: | 19 April 2021 |
| Open Access Version: | |
| URI: | https://wrap.warwick.ac.uk/124383/ |
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