PBPK Modelling of Dexamethasone in Patients With COVID-19 and Liver Disease

Montanha, Maiara Camotti, Cottura, Nicolas ORCID: 0000-0003-3083-2249, Booth, Michael, Hodge, Daryl ORCID: 0000-0003-2288-7020, Bunglawala, Fazila, Kinvig, Hannah, Granana-Castillo, Sandra, Lloyd, Andrew, Khoo, Saye ORCID: 0000-0002-2769-0967 and Siccardi, Marco ORCID: 0000-0002-3539-7867 (2022) PBPK Modelling of Dexamethasone in Patients With COVID-19 and Liver Disease. FRONTIERS IN PHARMACOLOGY, 13. 814134-.

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Official URL: http://dx.doi.org/10.3389/fphar.2022.814134

Abstract

The aim of the study was to apply Physiologically-Based Pharmacokinetic (PBPK) modelling to predict the effect of liver disease (LD) on the pharmacokinetics (PK) of dexamethasone (DEX) in the treatment of COVID-19. A whole-body PBPK model was created to simulate 100 adult individuals aged 18-60 years. Physiological changes (e.g., plasma protein concentration, liver size, CP450 expression, hepatic blood flow) and portal vein shunt were incorporated into the LD model. The changes were implemented by using the Child-Pugh (CP) classification system. DEX was qualified using clinical data in healthy adults for both oral (PO) and intravenous (IV) administrations and similarly propranolol (PRO) and midazolam (MDZ) were qualified with PO and IV clinical data in healthy and LD adults. The qualified model was subsequently used to simulate a 6 mg PO and 20 mg IV dose of DEX in patients with varying degrees of LD, with and without shunting. The PBPK model was successfully qualified across DEX, MDZ and PRO. In contrast to healthy adults, the simulated systemic clearance of DEX decreased (35%-60%) and the plasma concentrations increased (170%-400%) in patients with LD. Moreover, at higher doses of DEX, the AUC ratio between healthy/LD individuals remained comparable to lower doses. The exposure of DEX in different stages of LD was predicted through PBPK modelling, providing a rational framework to predict PK in complex clinical scenarios related to COVID-19. Model simulations suggest dose adjustments of DEX in LD patients are not necessary considering the low dose administered in the COVID-19 protocol.

Item Type:	Article
Uncontrolled Keywords:	dexamethasone, liver disease, COVID-19, PBPK modelling, pharmacokinetic (PK)
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	22 Feb 2022 12:17
Last Modified:	18 Jan 2023 21:11
DOI:	10.3389/fphar.2022.814134
Open Access URL:	https://doi.org/10.3389/fphar.2022.814134
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3149429