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Statistical tools for dose individualization of mycophenolic acid and tacrolimus co-administered during the first month after renal transplantation

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Musuamba Tshinanu, Flora [UCL] Mourad, Michel [UCL] Haufroid, Vincent [UCL] De Meyer, Martine [UCL] Capron, Arnaud [UCL] Delattre, Isabelle [UCL] Verbeeck, Roger-K. [UCL] Wallemacq, Pierre [UCL]

AIM: 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. METHODS: 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. RESULTS: The following models were retained: AUC(0,12 h) = 16.5 + 4.9 × C1.5 + 6.7 × C3.5 (r(2) = 0.82, rRMSE = 9%, with simulations and r(2) = 0.66, rRMSE = 24%, with observed data) and AUC(0,12 h) = 24.3 + 5.9 × C1.5 + 12.2 × C3.5 (r(2) = 0.94, rRMSE = 12.3%, with simulations r(2) = 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: r(2) = 0.90, rRMSE = 13% and r(2) = 0.97, rRMSE = 5% with simulations for MPA and TAC, respectively and r(2) = 0.75, rRMSE = 11% and r(2) = 0.83, rRMSE = 7% with observed data for MPA and TAC, respectively. CONCLUSION: Statistical tools were developed for simultaneous MPA and TAC therapeutic drug monitoring. They can be incorporated in computer programs for patient dose individualization.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2013
Language Anglais
Journal information "British Journal of Clinical Pharmacology" - Vol. 75, no. 5, p. 1277-1288 (2013)
Peer reviewed yes
Publisher Wiley-Blackwell Publishing Ltd. ((United Kingdom) Oxford)
issn 0306-5251
e-issn 1365-2125
Publication status Publié
Affiliations UCL - (SLuc) Service de biochimie médicale
UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation
UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology
UCL - SSS/LDRI - Louvain Drug Research Institute
UCL - (SLuc) Service de chirurgie et transplantation abdominale
UCL - (SLuc) Centre de toxicologie clinique
UCL - (SLuc) Service de biochimie médicale
Keywords Bayesian estimators ; dose individualization ; multiple linear regression ; mycophenolate ; optimality ; tacrolimus
Links
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Bibliographic reference Musuamba Tshinanu, Flora ; Mourad, Michel ; Haufroid, Vincent ; De Meyer, Martine ; Capron, Arnaud ; et. al. Statistical tools for dose individualization of mycophenolic acid and tacrolimus co-administered during the first month after renal transplantation. In: British Journal of Clinical Pharmacology, Vol. 75, no. 5, p. 1277-1288 (2013)
Permanent URL http://hdl.handle.net/2078.1/127310