Large scale analysis of routine dose adjustments of mycophenolate mofetil based on global exposure in renal transplant patients.

International audienceBACKGROUND: : We report a feasibility study based on our large-scale experience with mycophenolate mofetil dose adjustment based on mycophenolic acid interdose area under the curve (AUC) in renal transplant patients. METHODS: : Between 2005 and 2010, 13,930 requests for 7090 different patients (outside any clinical trial) were posted by more than 30 different transplantation centers on a free, secure web site for mycophenolate mofetil dose recommendations using three plasma concentrations and Bayesian estimation. RESULTS: : This retrospective study showed that 1) according to a consensually recommended 30- to 60-mg*h/L target, dose adjustment was needed for approximately 35% of the patients, 25% being underexposed with the highest proportion observed in the first weeks after transplantation; 2) when dose adjustment had been previously proposed, the subsequent AUC was significantly more often in the recommended range if the dose was applied than not at all posttransplantation periods (72-80% vs. 43-54%); and 3) the interindividual AUC variability in the "respected-dose" group was systematically lower than that in the "not respected-dose" group (depending on the posttransplantation periods; coefficient of variation %, 31-41% vs 49-70%, respectively). Further analysis suggested that mycophenolic acid AUC should best be monitored at least every 2 weeks during the first month, every 1 to 3 months between months 1 and 12, whereas in the stable phase, the odds to be still in the 30- to 60-mg*h/L range on the following visit was still 75% up to 1 year after the previous dose adjustment. CONCLUSION: : This study showed that the monitoring of mycophenolate mofetil on the basis of AUC measurements is a clinically feasible approach, apparently acceptable by the patients, the nurses, and the physicians owing to its large use in routine clinics

Pharmacokinetic modelling and development of Bayesian estimators for therapeutic drug monitoring of mycophenolate mofetil in reduced-intensity haematopoietic stem cell transplantation.

International audienceBACKGROUND: Mycophenolate mofetil, a prodrug of mycophenolic acid (MPA), is used during non-myeloablative and reduced-intensity conditioning haematopoetic stem cell transplantation (HCT) to improve engraftment and reduce graft-versus-host disease (GVHD). However, information about MPA pharmacokinetics is sparse in this context and its use is still empirical. OBJECTIVES: To perform a pilot pharmacokinetic study and to develop maximum a posteriori Bayesian estimators (MAP-BEs) for the estimation of MPA exposure in HCT. PATIENTS AND METHODS: Fourteen patients administered oral mycophenolate mofetil 15 g/kg three times daily were included. Two consecutive 8-hour pharmacokinetic profiles were performed on the same day, 3 days before and 4 days after the HCT. One 8-hour pharmacokinetic profile was performed on day 27 after transplantation. For these 8-hour pharmacokinetic profiles, blood samples were collected predose and 20, 40, 60, 90 minutes and 2, 4, 6 and 8 hours post-dose. Using the iterative two-stage (ITS) method, two different one-compartment open pharmacokinetic models with first-order elimination were developed to describe the data: one with two gamma laws and one with three gamma laws to describe the absorption phase. For each pharmacokinetic profile, the Akaike information criterion (AIC) was calculated to evaluate model fitting. On the basis of the population pharmacokinetic parameters, MAP-BEs were developed for the estimation of MPA pharmacokinetics and area under the plasma concentration-time curve (AUC) from 0 to 8 hours at the different studied periods using a limited-sampling strategy. These MAP-BEs were then validated using a data-splitting method. RESULTS: The ITS approach allowed the development of MAP-BEs based either on 'double-gamma' or 'triple-gamma' models, the combination of which allowed correct estimation of MPA pharmacokinetics and AUC on the basis of a 20 minute-90 minute-240 minute sampling schedule. The mean bias of the Bayesian versus reference (trapezoidal) AUCs was 20%. AIC was systematically calculated for the choice of the most appropriate model fitting the data. CONCLUSION: Pharmacokinetic models and MAP-BEs for mycophenolate mofetil when administered to HCT patients have been developed. In the studied population, they allowed the estimation of MPA exposure based on three blood samples, which could be helpful in conducting clinical trials for the optimization of MPA in reduced-intensity HCT. However, prior studies will be needed to validate them in larger populations

Pharmacocinétique du tacrolimus chez le transplanté pulmonaire atteint ou non de mucoviscidose

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

Pharmacocinétique et suivi thérapeutique pharmacologique de la ciclosporine en transplantation d'organes solides

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

Current role of LC-MS in therapeutic drug monitoring

Abstract The role of liquid chromatography coupled with mass spectrometry (LC-MS) techniques in routine therapeutic drug monitoring activity is becoming increasingly important. This paper reviews LC-MS methods published in the last few years for certain classes of drugs subject to therapeutic drug monitoring: immunosuppressants, antifungal drugs, antiretroviral drugs, antidepressants and antipsychotics. For each class of compounds, we focussed on the most interesting methods and evaluated the current role of LC-MS in therapeutic drug monitoring

[Level of evidence for therapeutic drug monitoring of everolimus].

International audienceEverolimus has proven efficacy for prevention of rejection in adult de novo renal and cardiac transplant recipient in combination with ciclosporine and corticosteroids. Therapeutic drug monitoring (TDM) with target trough concentration (C0) value from 3 to 8 µg/L has been proposed. Through a systematic review of the literature, this work explored a level of recommendation for this TDM. Everolimus exhibits both wide interindividual pharmacokinetic variability and poor relationship between dose and exposure. A good relationship has been reported between C0 values and global exposure to the drug (i.e. AUC). Although C0 > 3 µg/L has been associated with a decreased incidence of rejection, the upper limit of 8 µg/L has never been formally validated. No clinical trial testing other exposure indices or comparing efficacy and/or toxicity of everolimus therapy with and without TDM has been published so far. Consequently the level of recommendation for everolimus monitoring is "recommended"

Cyclosporine therapeutic window evaluation by Chebyshev\u27s inequality method in kidney recipients

Objective: The aim of this study was to identify a cyclosporine therapeutic range for kidney recipients.Materials and methods: The cyclosporine exposure level was based on the calculation of the mean area under the concentration-time curve AUC(0–12). The AUC(0–12) was estimated using a Bayesian estimator and a 3-point limited sampling strategy. Cyclosporine exposure levels were obtained from 3 blood samples: 0, 1, and 3 h postdose; and analyses were performed using a liquid chromatography–tandem mass spectrometry method. The therapeutic window of cyclosporine was calculated by the Chebyshev\u27s inequality method with a 99% guarantee (a = 0.01) using the IBM SPSS Statistics 20 software.Results: It was found that the therapeutic window of cyclosporine estimated by the Cheby- shev\u27s inequality method and put on the AUC(0–12) exposure lies in the ranges from 2.84– 3.13 mg h/L with the 99% confidence for the patients with the target AUC(0–12) exposure of 3.8 mg h/L (posttransplantation time >1 year). The therapeutic window of cyclosporine differs in different posttransplantation time groups: the estimated AUC exposure range in the group of patients who have a graft longer than 5 years is 2.70–2.98 mg h/L, and the estimated AUC exposure range in the group of patients who have a graft for 1–5 years is 3.05–3.75 mg h/L.Conclusions: Chebyshev\u27s inequality could be an appropriate and more precise method to determine the therapeutic window for cyclosporine in kidney recipients than the target AUC(0–12) value and further studies should be conducted to evaluate patients with postoperative time <1 year

Lessons from routine dose adjustment of tacrolimus in renal transplant patients based on global exposure.

International audienceOBJECTIVES: Since 2007, a number of transplantation centers have been routinely using an expert system for tacrolimus (TAC) dose adjustment in kidney allograft recipients, based on PK modeling and Bayesian estimation for area-under-the-curve (AUC) determination. This has allowed the setting up of a large database of TAC pharmacokinetic profiles and AUC values, a part of which was analyzed here. METHODS: We retrospectively studied 2030 requests posted by 21 different centers for routine TAC dose adjustment in 1000 different adult renal transplant patients (not enrolled in any kind of concentration-controlled clinical trial). For each request, the following information was obtained: time elapsed since transplantation, TAC daily dose, calculated AUC, and trough concentration (C0). RESULTS: The dose-standardized exposure to TAC significantly and progressively increased in the months after transplantation: from month (M) 1 to M9 C0/dose increased from 2.33 to 3.44 mcg*L(1)*mg(1) and AUC/dose from 43.1 to 64.2 mcg*h(1)*L(1)*mg(1), respectively. On the contrary, in patients beyond the first year whose C0 or AUC was in the target range, the odds of remaining in this range were high for a long time period, suggesting a low intrapatient variability in the stable phase. Regression analyses showed that the correlation between C0 and AUC was better in the first 3-month period (r(2) = 0.76) than later on (r(2) ≤ 0.67). Using the regression equations obtained, AUC ranges corresponding to different applicable C0 targets were calculated. CONCLUSIONS: From a large number of kidney graft recipients, we have estimated the relationships between C0 and AUC, modeled the evolution of TAC exposure with time and defined AUC targets that could be useful to lead further controlled-concentration trials and improve routine TAC therapeutic drug monitoring