Statistical tools for dose individualization of mycophenolic acid and tacrolimus co-administered during the first month after renal transplantation
Article first published online: 8 APR 2013
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 75, Issue 5, pages 1277–1288, May 2013
How to Cite
Musuamba, F. T., Mourad, M., Haufroid, V., De Meyer, M., Capron, A., Delattre, I. K., Verbeeck, R. K. and Wallemacq, P. (2013), Statistical tools for dose individualization of mycophenolic acid and tacrolimus co-administered during the first month after renal transplantation. British Journal of Clinical Pharmacology, 75: 1277–1288. doi: 10.1111/bcp.12007
- Issue published online: 8 APR 2013
- Article first published online: 8 APR 2013
- Accepted manuscript online: 17 OCT 2012 06:24AM EST
- Manuscript Accepted: 9 OCT 2012
- Manuscript Received: 30 JAN 2011
- Bayesian estimators;
- dose individualization;
- multiple linear regression;
To predict simultaneously the area under the concentration−time curve during one dosing interval [AUC(0,12 h)] for mycophenolic acid (MPA) and tacrolimus (TAC), when concomitantly used during the first month after transplantation, based on common blood samples.
Data were from two different sources, real patient pharmacokinetic (PK) profiles from 65 renal transplant recipients and 9000 PK profiles simulated from previously published models on MPA or TAC in the first month after transplantation. Multiple linear regression (MLR) and Bayesian estimation using optimal samples were performed to predict MPA and TAC AUC(0,12 h) based on two concentrations.
The following models were retained: AUC(0,12 h) = 16.5 + 4.9 × C1.5 + 6.7 × C3.5 (r2 = 0.82, rRMSE = 9%, with simulations and r2 = 0.66, rRMSE = 24%, with observed data) and AUC(0,12 h) = 24.3 + 5.9 × C1.5 + 12.2 × C3.5 (r2 = 0.94, rRMSE = 12.3%, with simulations r2 = 0.74, rRMSE = 15%, with observed data) for MPA and TAC, respectively. In addition, Bayesian estimators were developed including parameter values from final models and values of concentrations at 1.5 and 3.5 h after dose. Good agreement was found between predicted and reference AUC(0,12 h) values: r2 = 0.90, rRMSE = 13% and r2 = 0.97, rRMSE = 5% with simulations for MPA and TAC, respectively and r2 = 0.75, rRMSE = 11% and r2 = 0.83, rRMSE = 7% with observed data for MPA and TAC, respectively.
Statistical tools were developed for simultaneous MPA and TAC therapeutic drug monitoring. They can be incorporated in computer programs for patient dose individualization.