Personalized therapy for mycophenolate:Consensus report by the international association of therapeutic drug monitoring and clinical toxicology

When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.</p

Performance of the new mycophenolate assay based on IMPDH enzymatic activity for pharmacokinetic investigations and setup of Bayesian estimators in different populations of allograft recipients.

A new mycophenolate (MPA) assay based on the enzymatic activity of recombinant type II inosine monophosphate dehydrogenase (the pharmacological target of MPA) with excellent correlation with high-performance liquid chromatography has recently been released for the measurement of MPA plasma levels. This study aimed to (1) compare this new assay with liquid chromatography tandem mass spectrometry (LC-MS/MS) for MPA pharmacokinetic (PK) studies in different populations of allograft recipients given mycophenolate mofetil, (2) develop specific Bayesian estimators for this inhibition assay and test their accuracy, and (3) compare the resulting MPA area under the curve (AUC0-12h) estimates with those of Bayesian estimators developed based on the LC-MS/MS results. Sixty-four adult or pediatric, renal or lung transplant patients who were administered mycophenolate mofetil in association with cyclosporine, tacrolimus, or sirolimus at different post-transplant periods were enrolled as part of different PK studies. Eight hundred ninety-four patients' samples were analyzed in parallel with the enzymatic MPA assay and a reference LC-MS/MS method. Repeated analysis of quality control samples showed a mean difference of 6% between the 2 assays, whereas the results obtained in different populations of transplanted patients showed excellent correlation (r2 > 0.96) and small mean relative differences (2.0%-16.9%). The full profiles obtained with both assays were adequately fitted using either a 2-compartment model with 1 "gamma" absorption phase or a 1-compartment model with 2 gamma inputs. Several PK parameters were significantly affected by the analytical method used. Accurate Bayesian estimators could be specifically developed for the enzymatic MPA assay, using the same 3 concentration-time points (20 minutes, 1 hour, and 3 hours post dose) as with LC-MS/MS, with a median bias versus reference (trapezoidal) AUC0-12h values of -1.3% (range -45.2% to 40.4%), and 83% of the patients within +/-20% of the reference. These Bayesian estimates were significantly higher than those obtained with LC-MS/MS in patients on cyclosporine or sirolimus, but not in patients on tacrolimus.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Modèle animal d'étude chronopharmacocinétique des médicaments anticancéreux

LIMOGES-BU Médecine pharmacie (870852108) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Pharmacocinétique et suivi thérapeutique pharmacologique du mycophénolate mofétil dans le traitement anti-rejet de greffe.

LIMOGES-BU Médecine pharmacie (870852108) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Challenges in Hong Kong – Zhuhai – Macao Bridge (HZMB) Hong Kong Link Road Project

&lt;p&gt;The Hong Kong Link Road (HKLR) is part of the prominent structure, Hong Kong-Zuhai-Macao Bridge (HZMB), connecting 3 vibrant cities in Southern China. The works which are administered under Highways Department of HKSAR comprises design and construction of approximately 9km of viaducts. About 7km of the viaducts are marine structures with three navigation channels.&lt;/p&gt;&lt;p&gt;The basic structural form of the viaducts is precast segmental prestressed concrete box girder. The span length of the viaducts ranges from 35m to 180m. Balanced cantilever method is selected due to the variability of the span lengths and flexibility in construction. The piers consist of both cast- insitu and precast concrete structures. The viaducts are supported on bored piles with diameters ranging from 2.2m to 2.8m. Foundation in areas with complex geology such as fault zones has posed a major challenge to the job. Some piles are over 100m long due to complex geology.&lt;/p&gt;&lt;p&gt;This paper presents the challenges and solutions employed in the design and construction of the viaducts. It describes the prestressed schemes employed in both the decks and piers with special details used in the formation of monolithic deck-column connections. The three main Challenges on the project were the erection in open sea, the vicinity of the Airport and enverinmental constraints.&lt;/p&gt;</jats:p

Pharmacokinetics of mycophenolate mofetil in children with lupus and clinical findings in favour of therapeutic drug monitoring.

International audienceAIMS: The use of mycophenolate mofetil (MMF) in children with Systemic Lupus Erythematosus (SLE) is increasing. However, the clinical benefit of its monitoring has been scarcely studied, and little is known about its pharmacokinetics in this context. The objectives of the present study were: (i) to describe mycophenolic acid (MPA; the active moiety of MMF) pharmacokinetics; (ii) to develop a Bayesian estimator (BE) allowing the determination AUC (Area under the curve) from a limited number of blood samples; and (ii) to explore the relationships between exposure indices to MPA and the clinical status in children with SLE. METHODS: This was a retrospective study including 36 children with SLE, extracted from the expert system ISBA, for whom full- pharmacokinetic profiles of MPA were collected together with clinical data. A pharmacokinetic model and a BE were developed using an iterative two-stage Bayesian approach. ROC curve analyses and logistic regressions was used to investigate the association of exposure and active disease. RESULTS: A pharmacokinetic model and a BE were developed that allowed good AUC estimation performance (bias±SD=-0.02±0.15). ROC curve analyses showed that AUC/dose<0.06 and AUC<44 mg*h/L were associated with a good sensitivity and specificity for active disease (78%/94% and 94%/56% respectively). When introduced in a logistic regression model, AUC<44 mg.h/L and AUC/dose<0.06 were associated with an increased risk of active disease (OR=21.2[2.3-196.1], p=0.007; and OR [95%CI]=59.5[5.9-588.2], p=0.0005 respectively). CONCLUSIONS: The developed pharmacokinetics BE could be used to prospectively test the interest of MPA monitoring for limiting relapse of the disease or its progression

Evaluation of the mycophenolic acid exposure estimation methods used in the APOMYGERE, FDCC, and opticept trials

Background. Three randomized-controlled trials have examined the utility of mycophenolic acid (MPA) therapeutic drug monitoring in kidney transplant recipients. Each used a different methodology to estimate MPA exposure (pre-dose concentrations [C(0)], multiple regression-derived limited sampling strategies [LSSs], and Bayesian estimation in Opticept, FDCC [fixed dose versus concentration controlled] and APOMYGERE [adaption de Posologie du MMF en Greffe Renale] trials, respectively). Results were conflicting. This study aimed to compare the ability of these methodologies to predict AUC(0-12) in an independent cohort of kidney transplant recipients