Is there any relationship between the exposure to mycophenolic acid and the clinical status in children with lupus?

International audienc

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

Drug-specific risk and characteristics of lupus and vasculitis-like events in patients with rheumatoid arthritis treated with TNFi: results from BSRBR-RA

Objective: To compare the risk of lupus-like events (LLEs) and vasculitis-like events (VLEs) in tumour necrosis factor-α inhibitor (TNFi)-treated patients with rheumatoid arthritis (RA) to those receiving non-biological disease-modifying antirheumatic drugs (nbDMARDs). Methods: Patients were recruited to the British Society for Rheumatology Biologics Register—RA, a national prospective cohort study. Two cohorts recruited between 2001 and 2015: (1) patients starting first TNFi (adalimumab, etanercept, infliximab and certolizumab) (n=12 937) and (2) biological-naïve comparison cohort receiving nbDMARDs (n=3673). The risk of an event was compared between the two cohorts using Cox proportional-hazard models, adjusted using propensity scores. Rates of LLE/VLE were compared between TNFi and nbDMARD patients. Results: The crude incidence rates for LLEs were: TNFi 10/10 000 patient-years (pyrs) (95% CI 8 to 13) and nbDMARD 2/10 000 pyrs (95% CI 1 to 6); for VLEs: TNFi 15/10 000 pyrs (95% CI 12 to 19) and nbDMARD 7/10 000 pyrs (95% CI 4 to 12). The risk of both events was highest in the first year of TNFi treatment. After adjusting for differences in baseline characteristics, there was no difference in risk of LLEs (adjHR 1.86; 95% CI 0.52 to 6.58) or VLEs (adjHR 1.27; 95% CI 0.40 to 4.04) for TNFi compared to nbDMARD-treated patients. Infliximab conferred the highest overall risk, followed by etanercept, although 95% CIs overlapped following adjustment. Conclusions: In one of the largest biological registers, the absolute risk of both events is low. The addition of TNFi to nbDMARD does not alter the risk of either event in patients with RA selected for TNFi. This is the first study to assess the risk of these outcomes in a prospective, observational cohort

Population Pharmacokinetics of Tacrolimus in Adult Kidney Transplant Patients: Impact of CYP3A5 Genotype on Starting Dose.

Objectives: The aims of this study were to develop a population pharmacokinetic model of tacrolimus in adult kidney transplant recipients, to use this model to compare cytochrome P450 3A5 (CYP3A5) genotype-based initial dosing of tacrolimus with standard per-kilogram-based dosing, and to predict the best starting dose of tacrolimus based on patient genotype to achieve a trough concentration between 6 and 10 mu g/L by day 5 posttransplantation

Identification of Genes under Positive Selection Reveals Differences in Evolutionary Adaptation between Brown-Algal Species

Brown algae are an important taxonomic group in coastal ecosystems. The model brown algal species Ectocarpus siliculosus and Saccharina japonica are closely related lineages. Despite their close phylogenetic relationship, they vary greatly in morphology and physiology. To obtain further insights into the evolutionary forces driving divergence in brown algae, we analyzed 3,909 orthologs from both species to identify Genes Under Positive Selection (GUPS). About 12% of the orthologs in each species were considered to be under positive selection. Many GUPS are involved in membrane transport, regulation of homeostasis, and sexual reproduction in the small sporophyte of E. siliculosus, which is known to have a complex life cycle and to occupy a wide range of habitats. Genes involved in photosynthesis and cell division dominated the group of GUPS in the large kelp of S. japonica, which might explain why this alga has evolved the ability to grow very rapidly and to form some of the largest sporophytes. A significant number of molecular chaperones (e.g., heat-shock proteins) involved in stress responses were identified to be under positive selection in both species, potentially indicating their important roles for macroalgae to cope with the relatively variable environment of coastal ecosystems. Moreover, analysis of previously published microarray data of E. siliculosus showed that many GUPS in E. siliculosus were responsive to stress conditions, such as oxidative and hyposaline stress, whereas our RNA-seq data of S. japonica showed that GUPS in this species were most highly expressed in large sporophytes, which supports the suggestion that selection largely acts on different sets of genes in both marcoalgal species, potentially reflecting their adaptation to different ecological niches

Biogenesis of cytochrome b6 in photosynthetic membranes

In chloroplasts, binding of a c′-heme to cytochrome b6 on the stromal side of the thylakoid membranes requires a specific mechanism distinct from the one at work for c-heme binding to cytochromes f and c6 on the lumenal side of membranes. Here, we show that the major protein components of this pathway, the CCBs, are bona fide transmembrane proteins. We demonstrate their association in a series of hetero-oligomeric complexes, some of which interact transiently with cytochrome b6 in the process of heme delivery to the apoprotein. In addition, we provide preliminary evidence for functional assembly of cytochrome b6f complexes even in the absence of c′-heme binding to cytochrome b6. Finally, we present a sequential model for apo- to holo-cytochrome b6 maturation integrated within the assembly pathway of b6f complexes in the thylakoid membranes

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