Shan Pan1, Julia Korell2, Lisa K Stamp3, Stephen B Duffull4. 1. School of Pharmacy, University of Otago, Dunedin, New Zealand. shan.pan@otago.ac.nz. 2. Model Answers Pty Ltd, Brisbane, Australia. 3. Department of Medicine, University of Otago, Christchurch, New Zealand. 4. School of Pharmacy, University of Otago, Dunedin, New Zealand.
Abstract
PURPOSE: A pharmacokinetic (PK) model is available for describing the time course of the concentrations of methotrexate (MTX or MTXGlu1) and its active polyglutamated metabolites (MTXGlu2-5) in red blood cells (RBCs). In this study, we aimed to simplify the MTX PK model and to optimise the blood sampling schedules for use in future studies. METHODS: A proper lumping technique was used to simplify the original MTX RBC PK model. The sum of predicted RBC MTXGlu3-5 concentrations in both the simplified and original models was compared. The sampling schedules for MTXGlu3-5 or all MTX polyglutamates in RBCs were optimised using the Population OPTimal design (POPT) software. RESULTS: The MTX RBC PK model was simplified into a three-state model. The maximum of the absolute value of relative difference in the sum of predicted RBC MTXGlu3-5 concentrations over time was 6.3 %. A five blood sample design was identified for estimating parameters of the simplified model. CONCLUSIONS: This study illustrates the application of model simplification processes to an existing model for MTX RBC PK. The same techniques illustrated in our study may be adopted by other studies with similar interest.
PURPOSE: A pharmacokinetic (PK) model is available for describing the time course of the concentrations of methotrexate (MTX or MTXGlu1) and its active polyglutamated metabolites (MTXGlu2-5) in red blood cells (RBCs). In this study, we aimed to simplify the MTX PK model and to optimise the blood sampling schedules for use in future studies. METHODS: A proper lumping technique was used to simplify the original MTX RBC PK model. The sum of predicted RBC MTXGlu3-5 concentrations in both the simplified and original models was compared. The sampling schedules for MTXGlu3-5 or all MTX polyglutamates in RBCs were optimised using the Population OPTimal design (POPT) software. RESULTS: The MTX RBC PK model was simplified into a three-state model. The maximum of the absolute value of relative difference in the sum of predicted RBC MTXGlu3-5 concentrations over time was 6.3 %. A five blood sample design was identified for estimating parameters of the simplified model. CONCLUSIONS: This study illustrates the application of model simplification processes to an existing model for MTX RBC PK. The same techniques illustrated in our study may be adopted by other studies with similar interest.
Authors: Joakim Nyberg; Caroline Bazzoli; Kay Ogungbenro; Alexander Aliev; Sergei Leonov; Stephen Duffull; Andrew C Hooker; France Mentré Journal: Br J Clin Pharmacol Date: 2015-01 Impact factor: 4.335
Authors: Hesham S Al-Sallami; Song Lim Cheah; Shiou Yii Han; Joel Liew; Jin Lim; Mary Anne Ng; Hayneil Solanki; Run Jie Soo; Victoria Tan; Stephen B Duffull Journal: Eur J Clin Pharmacol Date: 2014-09-05 Impact factor: 2.953
Authors: Julia Korell; Lisa K Stamp; Murray L Barclay; Judith M Dalrymple; Jill Drake; Mei Zhang; Stephen B Duffull Journal: Clin Pharmacokinet Date: 2013-06 Impact factor: 6.447
Authors: Shan Pan; Lisa K Stamp; Stephen B Duffull; Murray L Barclay; Judith M Dalrymple; Jill Drake; Mei Zhang; Julia Korell Journal: Clin Pharmacokinet Date: 2014-12 Impact factor: 6.447
Authors: Karina I Halilova; Elizabeth E Brown; Sarah L Morgan; S Louis Bridges; Min-Ho Hwang; Donna K Arnett; Maria I Danila Journal: Int J Rheumatol Date: 2012-07-09