PBPK Modelling of Dexamethasone in Patients With COVID-19 and Liver Disease
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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.
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SciScore for 10.1101/2021.11.10.21266141: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources A whole body PBPK model constructed using Simbiology v. 5.8.2, a product of MATLAB® R2019a v. 9.6.0 (MathWorks, Natick, MA, USA 2013), was used to generate a cohort of 100 individuals aged 18-60 years (50% female and 50% male). MATLAB®suggested: (MATLAB, RRID:SCR_001622)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Though the PK of DEX in LD was successfully predicted, …
SciScore for 10.1101/2021.11.10.21266141: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Software and Algorithms Sentences Resources A whole body PBPK model constructed using Simbiology v. 5.8.2, a product of MATLAB® R2019a v. 9.6.0 (MathWorks, Natick, MA, USA 2013), was used to generate a cohort of 100 individuals aged 18-60 years (50% female and 50% male). MATLAB®suggested: (MATLAB, RRID:SCR_001622)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Though the PK of DEX in LD was successfully predicted, the model is characterized by some limitations. Although a direct and proportional relationship between CP score and increase in the plasma drug exposure was assume in the model, as demonstrated before by Johnson et al.,3 and also a linear correlation between portal vein shunt index and serum total bile acid concentrations in the peripheral vein,27 outliers individuals will not be represented by this assumption as demonstrated in supplementary table S2. Furthermore, the prevalence of spontaneous portosystemic shunt (SPS) increases as liver function injures, probably as an effect of damaging portal hypertension.26 However, large-SPS can be present in CP-A individuals as no SPS or small-SPS can be present in CP-C individuals.26 For this reason, the varying levels of portacaval-shunting associated with LD considered in the simulations was an aleatory linearly spaced range between 0.1 and 0.7. Other factors such as inter-individual variability, polymorphism, age (e.g., propranolol showed greater plasma level in elderly compared to young individuals),48 and unknown LD physiopathology mechanisms not represented in the model corroborate the challenge of qualifying the LD PBPK model against specific CP classifications.
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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