Exposure to mycophenolic acid better predicts immunosuppressive efficacy than exposure to calcineurin inhibitors in renal transplant patients.

A time-to-event model was developed to study the predictive factors of immunosuppressive efficacy in renal transplant patients and to investigate longitudinal calcineurin inhibitor (CNI) and mycophenolic acid (MPA) coexposures and patient characteristics as potential covariates. The efficacy end point included acute rejection (AR), graft loss, and death. Data from 222 patients were analyzed: 23 events were observed in 126 patients receiving cyclosporine as compared with 15 events in 96 patients receiving tacrolimus (P = 0.61) in the first 2 years posttransplantation. Each 1-mg·h/l increase of MPA area under the plasma concentration vs. time curve was associated with a 4% decreased risk of an event (hazard ratio (HR) = 0.96; 95% confidence interval (CI): 0.93-0.99). The onset of cytomegalovirus infection/disease significantly increased this risk (HR = 10.9; 95% CI: 6.5-21.7). Within the observed ranges, CNI exposures were not significantly associated with efficacy (i.e., AR, graft loss, and death). This work advocates the avoidance of unnecessary high CNI dosing and puts forward new arguments for MPA concentration monitoring.

Pharmacokinetics and exposure-effect relationships of capecitabine in elderly patients with breast or colorectal cancer.

PURPOSE: The aims of the present study were (1) to investigate the impact of great age on pharmacokinetics of capecitabine and its metabolites and (2) to evaluate the exposure-effect relationship of capecitabine in elderly patients. METHODS: Data collected from 20 elderly patients (75-92 years old) with breast or colorectal cancer who received oral capecitabine were analyzed. In order to study the old age effect on pharmacokinetics, data collected from two phase I studies involving 40 younger adults (<75 years old) with metastatic cancer who received oral capecitabine were added in the database. The population pharmacokinetic analysis was based on a four-compartment model describing the sequence of capecitabine and three of its metabolites. RESULTS: The absorption rate constant was found lower in the oldest patient group (≥75 years) compared with the youngest group, and the constant rate elimination of the 5-fluorouracil metabolite was found decreased over time (i.e., after 2 consecutive weeks of capecitabine administration). This time effect was not found different between the two age groups. In elderly patients, the exposure-safety analysis showed, from the second cycle of chemotherapy, significantly higher median exposures of capecitabine and its metabolites (5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine and 5-fluorouracil) in patients who experienced hand-foot syndrome compared with patients who did not. CONCLUSION: This study puts forward new arguments for the treatment of elderly cancer patients who could benefit from capecitabine chemotherapy with acceptable toxicity.

Impact of longitudinal exposure to mycophenolic acid on acute rejection in renal-transplant recipients using a joint modeling approach.

This study aimed to investigate the association between longitudinal exposure to mycophenolic acid (MPA) and acute rejection (AR) risk in the first year after renal transplantation, and to propose MPA exposure targets conditionally to this association. A joint model, adjusted for monitoring strategy (fixed-dose versus concentration-controlled) and recipient age, was developed; it combined a mixed-effects model to describe the whole pattern of MPA exposure (i.e. area under the concentration-time curve (AUC)) and a survival model. MPA AUC thresholds were determined using time-dependent receiver-operating characteristics (ROC) curves. Data from 490 adult renal-transplant recipients, representative of the general population of adult renal-transplant patients (i.e. including patients considered at low immunological risk-enrolled in the OPERA trial as well as second renal transplant and patients co-treated by either cyclosporine or tacrolimus), were analyzed. A significant association was found between the longitudinal exposure to MPA (MPA AUCs=f(t)) and AR (p=0.0081), and validated by bootstrapping. A significant positive correlation was observed between time post-transplantation and ROC thresholds which increased in average from 35 mg h/L in the first days to 41 mg h/L beyond six months post-transplantation (p<0.001). Using a new modeling approach which recognizes the repeated measures in a same patient, this study supports the association between MPA exposure and AR.

Population pharmacokinetics of mycophenolic acid in pediatric renal transplant patients using parametric and nonparametric approaches.

Mycophenolic acid (MPA) is an immunosuppressive drug widely used in the prevention of acute rejection in pediatric renal transplant recipients and is characterized by a wide inter-individual variability in its pharmacokinetics. The aim of this study was to compare population pharmacokinetic modeling of MPA in pediatric renal transplant recipients given mycophenolate mofetil, the ester prodrug of MPA, using parametric and nonparametric population methods. The data from 34 pediatric renal transplants (73 full pharmacokinetic profiles obtained on day 21, months 3, 6 and 9 post-transplant) were analyzed using both the nonlinear mixed-effect modeling (NONMEM) and nonparametric adaptive grid (NPAG) approaches, based on a two-compartment model with first order lagged time absorption and first order elimination. The predictive performance of the two models was evaluated in a separate group of 32 patients. Higher mean population parameter values and ranges of individual pharmacokinetic parameters were obtained with NPAG, especially for the elimination constant ke: mean 1.16 h(-1) (0.26-4.33 h(-1)) and 0.78 h(-1) (0.66-1.15 h(-1)) with NPAG and NONMEM, respectively. With NPAG, the skewness and kurtosis values for ke (2.03 and 7.80, respectively) were far from the theoretical values expected for normal distributions. Such a non-normal distribution could explain the high value of shrinkage (35%) obtained for this parameter with the parametric NONMEM method. Bayesian forecasting of mycophenolic acid exposure using the NPAG population pharmacokinetic parameters as priors yielded a better predictive performance, with a significantly smaller bias than with the NONMEM model (-1.68% vs -9.53%, p<0.0001). In conclusion, in the present study, NPAG was found to be the most adequate population pharmacokinetic method to describe the pharmacokinetics of MPA in pediatric renal transplant recipients.

Feasibility of, and critical paths for mycophenolate mofetil Bayesian dose adjustment: pharmacological re-appraisal of a concentration-controlled versus fixed-dose trial in renal transplant recipients.

The aim of this study was to analyze retrospectively and critically the different steps of the individual dose adjustment procedure employed in the concentration-controlled (CC) versus fixed-dose trial Apomygre, which showed that mycophenolate mofetil (MMF) dose adjustment using a limited sampling strategy significantly reduced the risk of treatment failures and acute rejection in renal transplants at one year posttransplantation. The number of AUCs performed during the study and circumstances of collection, time of blood sampling, Bayesian mycophenolic acid (MPA) area-under-the-curve (AUC) estimation procedures and physicians' compliance with MMF dose recommendations were retrospectively analyzed. 92% of AUCs scheduled over the study were actually performed. Sampling times were very well respected. Bayesian estimation of MPA exposure was done by the pharmacologists locally in accordance with the protocol instructions and the AUC estimates obtained were virtually all confirmed a posteriori. On the other hand, a second AUC estimated by multiple linear regression could only be provided for 84% of the profiles and showed a large overestimation with respect to Bayesian estimates for AUC values between 10 and 55mgh/L. In the CC arm, a very good physicians' compliance was observed (85%) and application of the dose recommendations led to higher values of AUCs (42.1+/-14.6mgh/L versus 36.7+/-16.3mgh/L, p=0.0035) and to more AUCs in the target range (69% versus 56%, p=0.0343) than when dose recommendations were not applied. By analyzing in detail the feasibility criteria of MMF Bayesian dose adjustment, this study highlighted the requirements for successful extrapolation of the Apomygre trial results to routine practice: (i) respect of the PK sampling time-windows; (ii) use of relevant tools for accurate drug exposure estimation and dose adjustment calculation; and (iii) good compliance of the physicians with regard to the recommended doses.