Prediction of Free from Total Mycophenolic Acid Concentrations in Stable Renal Transplant Patients: A Population-Based Approach

Colom, Helena; Andreu, Franc; Gelder, Teun van; Hesselink, Dennis A.; Winter, Brenda C M de; Bestard, Oriol; Torrás, Joan; Grinyó, Josep M.; Lloberas, Núria

doi:10.1007/s40262-017-0603-8

Cited by 22 publications

(34 citation statements)

References 55 publications

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“…Moreover, the calculated typical value of apparent clearance of tMPA (CL tMPA /F, 15.68 L/h) was also comparable to most of previously reported values (12.3-20.8 L/h) [17][18][19][20][21][22][23][24][25][26]. The population estimate of FU MPA in our study (1.84%) was similar to values reported by van Hest et al [28] and Colom et al [29] (2.03% and 1.93%, respectively). There were no obvious ethnic differences among different populations.…”

Section: Discussionsupporting

confidence: 92%

“…Furthermore, the uMPA and tMPA were connected using a linear protein binding model. Table 3, the population estimate of CL uMPA /F (852 L/h) was comparable to most of previously reported values in Caucasians (654-866 L/h) [27][28][29]. Moreover, the calculated typical value of apparent clearance of tMPA (CL tMPA /F, 15.68 L/h) was also comparable to most of previously reported values (12.3-20.8 L/h) [17][18][19][20][21][22][23][24][25][26].…”

Section: Discussionsupporting

confidence: 88%

“…population pharmacokinetics, unbound mycophenolic acid, linear protein binding, adult kidney transplant recipients tMPA population PK [17][18][19][20][21][22][23][24][25][26]. There are few investigations of the population PK characteristics of unbound MPA (uMPA) [27][28][29][30], the pharmacologically active component, due to the technical complexity of measurements. Furthermore, little is known in Chinese kidney transplant recipients.…”

Section: Introductionmentioning

confidence: 99%

“…The non-linear saturable protein binding model published previously [29,39] was also evaluated using equation 3.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Protein Binding on Exposure of Unbound and Total Mycophenolic Acid: A Population Pharmacokinetic Analysis in Chinese Adult Kidney Transplant Recipients

et al. 2020

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AIMS A population pharmacokinetic (PK) analysis was performed to: (1) characterise the PK of unbound and total mycophenolic acid (MPA) and its 7-O-mycophenolic acid glucuronide (MPAG) metabolite, and (2) identify the clinically significant covariates that cause variability in the dose-exposure relationship to facilitate dose optimisation.METHODS A total of 740 unbound MPA (uMPA), 741 total MPA (tMPA) and 734 total MPAG (tMPAG) concentration-time data from 58 Chinese kidney transplant patients were analysed using a nonlinear mixed-effect model. The influence of covariates was tested using a stepwise procedure. RESULTSThe PK of unbound MPA and MPAG were characterised by a two-and one-compartment model with first-order elimination, respectively. Apparent clearance of uMPA (CL uMPA /F) was estimated to be 852 L/h with a relative standard error (RSE) of 7.1%. The tMPA and uMPA were connected using a linear protein binding model, in which the protein binding rate constant (k B ) increased non-linearly with the serum albumin (ALB) concentration. The estimated k B was 53.4 /h (RSE, 2.3%) for patients with ALB of 40 g/L. In addition, model-based simulation showed that changes in ALB substantially affected tMPA but not uMPA exposure. CONCLUSIONS The established model adequately described the population PK characteristics of the uMPA, tMPA, and MPAG. The estimated CL uMPA /F and unbound fraction of MPA (FU MPA ) in Chinese kidney transplant recipients were comparable to those published previously in Caucasians. We recommend monitoring uMPA instead of tMPA to optimise mycophenolate mofetil (MMF) dosing for patients with lower ALB levels. Keywordspopulation pharmacokinetics, unbound mycophenolic acid, linear protein binding, adult kidney transplant recipients tMPA population PK [17][18][19][20][21][22][23][24][25][26]. There are few investigations of the population PK characteristics of unbound MPA (uMPA) [27][28][29][30], the pharmacologically active component, due to the technical complexity of measurements. Furthermore, little is known in Chinese kidney transplant recipients.Therefore, the aims of this study were to develop a population PK model to: (1) characterise the PK of uMPA, tMPA, and the metabolite MPAG, and (2) identify the clinically significant covariates that cause variability in the dose-exposure relationship to facilitate dose optimisation. Methods Study design and patientsThe data were obtained from two clinical studies conducted in 58 Chinese adult kidney transplant recipients [31,32]. All recipients received triple immunosuppressive therapy comprising MMF (CellCept®, Roche Pharma Ltd., Shanghai, China), CsA, and corticosteroids. The first study was an evaluation of the PK of MPA and MPAG during the early post-transplantation period conducted at Huashan Hospital, Fudan University [31]. MMF was initiated at 1500 mg/day from the day of the surgery. The second study was an open-label, multi-centre, two-phase, sequential, bioequivalence study conducted in stable kidney transplantation patients [32]. MMF dose wa...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

“…The non-linear saturable protein binding model published previously [29,39] was also evaluated using equation 3.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effect of Protein Binding on Exposure of Unbound and Total Mycophenolic Acid: A Population Pharmacokinetic Analysis in Chinese Adult Kidney Transplant Recipients

et al. 2020

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“…A total of 11 popPK models of MMF co‐administered with TAC were included for external evaluation after the literature retrieval. The details of the literature search process are provided in Appendix S1.…”

Section: Resultsmentioning

confidence: 99%

Systematic external evaluation of published population pharmacokinetic models of mycophenolate mofetil in adult kidney transplant recipients co‐administered with tacrolimus

Zhang

Sheng

Liu

et al. 2019

Brit J Clinical Pharma

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AIMSVarious mycophenolate mofetil (MMF) population pharmacokinetic (popPK) models have been developed to describe its PK characteristics and facilitate its optimal dosing in adult kidney transplant recipients co-administered with tacrolimus. However, the external predictive performance has been unclear. Thus, this study aimed to comprehensively evaluate the external predictability of published MMF popPK models in such populations and investigate the potential influencing factors. METHODSThe external predictability of qualified popPK models was evaluated using an independent dataset. The evaluation included prediction-and simulation-based diagnostics, and Bayesian forecasting. In addition, factors influencing model predictability, especially the impact of structural models, were investigated. RESULTSFifty full PK profiles from 45 patients were included in the evaluation dataset and 11 published popPK models were identified and evaluated. In prediction-based diagnostics, the prediction error within ±30% was less than 50% in most published models. The prediction-and variability-corrected visual predictive check and posterior predictive check showed large discrepancies between British Journal of Clinical Pharmacology Br J Clin Pharmacol (2019) 85 746-761 746 the observations and simulations in most models. Moreover, the normalized prediction distribution errors of all models did not follow a normal distribution. Bayesian forecasting demonstrated an improvement in the model predictability. Furthermore, the predictive performance of two-compartment (2CMT) models incorporating the enterohepatic circulation (EHC) process was not superior to that of conventional 2CMT models. CONCLUSIONSThe published models showed large variability and unsatisfactory predictive performance, which indicated that therapeutic drug monitoring was necessary for MMF clinical application. Further studies incorporating potential covariates need to be conducted to investigate the key factors influencing model predictability of MMF. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Population pharmacokinetic analyses are widely used to describe mycophenolate mofetil pharmacokinetic characteristics in adult kidney transplant recipients co-administered with tacrolimus and facilitate dose individualization. • Model transferability can be influenced by centre-related factors, and it is unclear whether these models can be appropriately extrapolated to other centres. WHAT THIS STUDY ADDS• We comprehensively evaluated the external predictability of published models using an independent dataset.• The published models performed unsatisfactorily in prediction-and simulation-based diagnostics.• The investigation of the impact of model structure did not show that incorporating the EHC process could improve predictive performance. External evaluation of MMF popPK models Br J Clin Pharmacol (2019) 85 746-761 747 External evaluation of MMF popPK models Br J Clin Pharmacol (2019) 85 746-761 749 External evaluation of MMF popPK models Br J Clin Pharmacol (2019) 85 746-761 759

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Utility of salivary mycophenolic acid concentration monitoring: Modeling and Monte Carlo validation approach

Catić‐Đorđević

Stefanović

Pavlović

et al. 2022

Pharmacology Res & Perspec

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The results of the previous studies demonstrated an association between mycophenolic acid (MPA) exposure, serum albumin level (ALB), and adverse effects in kidney transplant patients. The aim was the identification of mathematical correlation and association between both, total and unbound MPA concentration in relation to ALB, body mass (BM), age and estimated glomerular filtration rate (eGFR) in stable kidney transplant recipients. Furthermore, investigation was conducted with the aim to clarify the role of salivary concentration (C SAL ) of MPA in adverse effect profile. In order to analyze the association between total and salivary concentration of MPA in relation to ALB, BM, age and eGFR, a least squares method for determining the correlation between these parameters was performed. In addition, derived mathematical model based on experimental data can also be performed and simulated through the Monte Carlo (MC) approach. Adverse effects were grouped according to the nature of symptoms and scored by a previously published validated system. Numerically calculated values of C SAL from the models [C SAL = f (ALB, BM, age, eGFR, C P ) = a 00 + a 10 *(ALB, BM, age, eGFR) + a 01 *C P ] were then compared with those from validation set of patients, where the best fitting model was for ALB [C SAL = 54.96–1.64*ALB +13.4*C P ]. Adverse effects estimation showed the difference in esthetic score, positively correlated with C SAL in the lower ALB group (145.41 ± 219.02 vs. 354.08 ± 262.19; with statistical significance p = .014) and almost significant for gastrointestinal score (167.69 ± 174.79 vs. 347.55 ± 320.95; p = .247). The study showed that C SAL MPA may contribute to management of adverse effects, but these findings require confirmation of clinical utility.

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Prediction of Free from Total Mycophenolic Acid Concentrations in Stable Renal Transplant Patients: A Population-Based Approach

Abstract: A reliable protein-binding population PK model was developed for prediction of fMPA or tMPA from each other and for dose guiding in stable renal transplant recipients.

Cited by 22 publications

References 55 publications

Effect of Protein Binding on Exposure of Unbound and Total Mycophenolic Acid: A Population Pharmacokinetic Analysis in Chinese Adult Kidney Transplant Recipients

Effect of Protein Binding on Exposure of Unbound and Total Mycophenolic Acid: A Population Pharmacokinetic Analysis in Chinese Adult Kidney Transplant Recipients

Systematic external evaluation of published population pharmacokinetic models of mycophenolate mofetil in adult kidney transplant recipients co‐administered with tacrolimus

Utility of salivary mycophenolic acid concentration monitoring: Modeling and Monte Carlo validation approach

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