Prediction of liver volume – a population‐based approach to meta‐analysis of paediatric, adult and geriatric populations – an update

Abstract

Liver volume is a critical scaling factor for predicting drug clearance in physiologically based pharmacokinetic modelling and for both donor/recipient graft size estimation in liver transplantation. The accurate and precise estimation of liver volume is therefore essential. The objective here was to extend an existing meta-analysis using a non-linear mixed effects modelling approach for the estimation of liver volume to other race groups and paediatric and geriatric populations. Interrogation of the PubMed® database was undertaken using a text string query to ensure as objective a retrieval of liver volume data for the modelling exercise as possible. Missing body size parameters were estimated using simulations from the Simcyp Simulator V13R1 for an age and ethnically appropriate population. Non-linear mixed effect modelling was undertaken in Phoenix 1.3 (Certara) utilizing backward deletion and forward inclusion of covariates from fully parameterized models. Existing liver volume models based on body surface area (BSA) and body weight and height were implemented for comparison. The extension of a structural model using a BSA equation and incorporating the Japanese race and age as covariates and exponents on LV0 (θ ) and body surface area (θ ), respectively, delivered a comparatively low objective function value. Bootstrapping of the original dataset revealed that the confidence intervals (2.5-97.5%) for the fitted (theta) parameter estimates were bounded by the bootstrapped estimates of the same. In conclusion, extension and re-parameterization of the existing Johnson model adequately describes changes in liver volume using the body surface area in all investigated populations. Copyright © 2017 John Wiley & Sons, Ltd.

Implementation of a Physiologically Based Pharmacokinetic Modeling Approach to Guide Optimal Dosing Regimens for Imatinib and Potential Drug Interactions in Paediatrics

“…Interestingly, this equation was in concordance with an allometric weight model with an exponent of ¾ in estimating liver volume from infants to adolescents (Fanta et al, 2007). The correlation between liver volume and BSA alone was superior than that with other covariates , in agreement with the findings of a nonlinear mixed effect modeling approach (Small et al, 2017). All the ontogeny equations used in the current study were driven by postnatal age.…”

Are body surface area based estimates of liver volume applicable to children with overweight or obesity? An in vivo validation study

“…MPPGL values are available from in vitro studies 8 and may vary with factors such as age 8,9 . Reliable estimates of liver volumes in children are needed in PBPK model development to help estimate hepatic capacity for drug clearance and thus systemic drug concentrations for children [10][11][12] .…”

Physiologically Based Pharmacokinetic Modeling of Transdermal Selegiline and Its Metabolites for the Evaluation of Disposition Differences between Healthy and Special Populations

“…PBPK modeling and simulations were performed using the Simcyp population based Simulator version 18, release 2 (Certara, Sheffield, UK). The virtual populations for healthy volunteers (Sim-Healthy Volunteers [ 29 ]), geriatric populations (Sim-Geriatric NEC [ 30 , 31 ]), moderate and severe renally impaired populations (Sim-Renal GFR 30–60 and Sim-Renal GFR < 30 [ 32 ]), and moderate and severe hepatic impaired populations (Sim-Cirrhosis Child Pugh-B and Sim-Cirrhosis Child Pugh-C [ 33 ]) were used for subject sampling. The macroglobulin protein concentrations in healthy (males: 3.95 μM; 17.7% CV and females: 4.47 μM; 14.4% CV) [ 34 ], renally impaired (males: 7.27 μM; 37.3% CV and females: 8.21 μM; 21.9% CV) [ 35 ], and hepatic impaired population (males: 5.488 μM; 23.88% CV and females: 5.23 μM; 19.2% CV) [ 35 ] were defined based on the literature reports.…”