Mathematical modelling of gene delivery in patients with haemophilia B

• Published in: Chemical engineering science Vol. 281; p. 119073
• Main Authors: Jamili, Elnaz, Nathwani, Amit C., Dua, Vivek
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 05.11.2023
• Subjects: Efficacy; Gene delivery; Initial dose selection; Pharmacokinetic/pharmacodynamic modelling; Toxicity; Gene delivery; Efficacy; Pharmacokinetic/pharmacodynamic modelling; Toxicity; Initial dose selection
• ISSN: 0009-2509
• DOI: 10.1016/j.ces.2023.119073

•A promising platform for gene delivery clinical trial simulations is provided.•PK/PD analysis is performed for both individual and population modelling approaches.•Model predictions are consistent with the clinical data for haemophilia patients.•A simulation-based modelling approach is proposed to guide initial dose selection.•Simulations show that the increase in FIX activity and ALT level is dose-dependent. Haemophilia B 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 an 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 the 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 from 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 to provide clinicians with better tools to simplify the decision-making process for designing more effective treatment plans.