Ben G Small*, Bernd Wendt*, Masoud Jamei, Trevor N Johnson * Joint first author contribution
Simcyp (a Certara Company), Sheffield, UK
Objectives: Liver volume is a critical parameter for both donor / recipient graft size and as a scaling factor for drug clearance in physiologically-based pharmacokinetic modelling; therefore having an accurate and precise estimation of this parameter is essential. The objective of this study was to extend an existing meta-analysis for the estimation of liver volume to other ethnic groups and paediatric and geriatric specific populations using non-linear mixed effect modelling techniques.
Methods: Extraction of medical subject heading terms from 64 publications assessing the measurement and / or prediction of liver volume allowed construction of a search string that enabled the objective retrieval of records from the PubMed® database. Parsing of retrieved records to ensure relevance to liver volume assessment was achieved by filtering records against exclusion criteria. Missing body size parameters were simulated within the Simcyp Simulator v14.1 for an age appropriate population. Non-linear mixed effect modelling was undertaken in Phoenix 1.3 (Pharsight) utilising backward deletion and forward inclusion of covariates from fully parameterised models. Existing liver volume models based on body surface area (1, 2) and bodyweight & height (3) were implemented for the purposes of comparison.
Results: Extension of a structural model predicated on a BSA equation and incorporating the Japanese race and age as co-variates and exponents on LV0 (θBaseline) and body surface area (θBSA) respectively delivered a comparatively low OFV. 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.
Conclusions: These results demonstrate that extension and re-parameterisation of the existing Johnson model provides an adequate descriptor of body surface area-dependent changes in liver volume.
References:
1. Johnson TN et al. Liver transplantation. 2005;11:1481-93.
2. Urata K et al. Hepatology1995;21:1317-21.
3. Yu HC et al. Liver Transplantation. 2004;10:779-83.
Reference: PAGE 25 () Abstr 6036 [www.page-meeting.org/?abstract=6036]
Poster: Methodology - Covariate/Variability Models