Jamili, Elnaz;
Nathwani, Amit C;
Dua, Vivek;
(2023)
Mathematical modelling of gene delivery in patients with haemophilia B.
Chemical Engineering Science
, 281
, Article 119073. 10.1016/j.ces.2023.119073.
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Abstract
Type B haemophilia is a bleeding disorder resulting from a deficiency of coagulation factor IX (FIX). Although gene therapy is a potentially curative treatment option, optimising the dosing of therapeutic genes for patients remains a challenge. Detailed simulation of gene delivery systems is required for improved understanding of the system. Hence, the purpose of this paper is to develop a modelling framework to predict the physiological response of a subject affected by type B haemophilia to a dose of vector. To address this, an integrated pharmacokinetic/pharmacodynamic (PK/PD) modelling platform was developed based on in vivo clinical data for three patients with severe haemophilia B whose functional plasma levels of FIX are less than 1% of the normal value. The plasma FIX activity was considered as the pharmacological effect while the level of serum alanine aminotransferase (ALT) demonstrated the hepatocellular toxicity. Both an individual-based modelling approach and a population modelling approach were used to estimate the physiological parameters of the developed PK/PD models. The models were then validated using data of the clinical study before being used in a simulation-based modelling approach to provide dosing recommendations. The results obtained from the study demonstrate a good prediction of the pharmacokinetics and pharmacodynamics of the vector. Model-based simulations were subsequently performed to guide initial dose selection in order to provide clinicians with better tools to make the decision-making process simpler for designing more effective treatment plans.
| Type: | Article |
|---|---|
| Title: | Mathematical modelling of gene delivery in patients with haemophilia B |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ces.2023.119073 |
| Publisher version: | https://doi.org/10.1016/j.ces.2023.119073 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Gene delivery, Initial dose selection, Pharmacokinetic/pharmacodynamic modelling, Toxicity, Efficacy |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Chemical Engineering |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10174097 |
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