Peggy Gandia

Development of a Bayesian estimator for the therapeutic drug monitoring of mycophenolate mofetil in children with idiopathic nephrotic syndrome.

The use of mycophenolate mofetil (MMF) in children with idiopathic nephrotic syndrome (INS) 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 study and model the pharmacokinetics of mycophenolic acid (MPA; the active moiety of MMF) in paediatric patients with INS given MMF, at all stages of the disease; (ii) to develop a Bayesian estimator (MAP-BE) for individual inter-dose area under the concentration-time curve (AUC) prediction in this population, using a limited blood sampling strategy (LSS). Full-pharmacokinetic (PK) profiles of MPA collected in paediatric inpatients with INS already treated with a maintenance immunosuppressive therapy based on MMF (with no calcineurin inhibitors; CNI) were studied. A classical iterative two-stage (ITS) method was applied to model the data and develop MAP-BEs using a one-compartment open model where the absorption is described by a double gamma law allowing the description of a potential enterohepatic recirculation. The performance of the MAP-BE developed for individual exposure assessment was evaluated by the bias and precision of predicted AUCs with respect to measured, trapezoidal AUCs (reference value), and by the proportion of predicted AUCs with absolute error >20%. These PK tools were tested in an independent group of patients. Sixty PK profiles of MPA from children receiving MMF in association to corticosteroids or given alone were included in the study. Forty-five of these PK profiles were used to develop a PK model and a MAP-BE, and 15 for their validation. In the building group, the PK model fitted accurately the PK profiles of MPA: mean residual error of modelled vs. reference AUC was m±SD=-0.015±0.092 (range: -0.153 to 0.204). The MAP-BE which allowed the estimation of MPA AUC on the basis of a 20 min-60 min-180 min LSS was then developed. In the independent group of patients, its mean residual error vs. reference AUCs was m±SD=-0.036±0.145 (range: -0.205 to 0.189). Thus, a PK model and its derived MAP-BE for MMF (without any associated CNI) when given to children with INS have been developed. Clinical trials using these PK tools could test the potential impact of the therapeutic drug monitoring of MMF based on the AUC on the clinical evolution of INS.

Inhibition of T-cell activation and proliferation by mycophenolic acid in patients awaiting liver transplantation: PK/PD relationships.

Mycophenolic acid (MPA) plasma concentrations were reported to be associated with a decrease in T-cell proliferation, and in both IL-2 α-chain (CD25) and transferin receptor (CD71) expression. The aim of this study was to confirm, quantify and model these PK/PD relationships. Full profiles of MPA plasma concentrations, T-cell proliferation, intracytoplasmic IL-2 and TNF-α expression, and both CD71 and CD25 expression were collected over the 12h after dosing in 10 patients on the waiting list for liver transplantation. Data were analyzed using NONMEM(®). Both CD25 and CD71 expression and T cell proliferation clearly decreased (median of decrease from baseline 62%, 68% and 94%, respectively) with increasing MPA concentrations, in contrast to IL-2 and TNF-α expression. The CD25 and CD71 baseline expression (E(0)) and maximum effect (E(max)) were correlated with the E(0) and E(max) values of T-cell proliferation (r(2)=0.509 and r(2)=0.622, respectively). The CD25, CD71 expression and T-cell proliferation profiles were adequately fitted using a sigmoid inhibitory E(max) model. Low estimated values (≤2 mg/L) for 50% inhibitory MPA concentrations were obtained. This study confirmed a transient MPA concentration-dependent decrease in T-cells expressing CD25 and CD71 and a strong reduction of T-cell proliferation and showed that CD25 and CD71 expression was correlated with T-cell proliferation.

Pharmacodynamic effects of cinacalcet after kidney transplantation: once- versus twice-daily dose

BACKGROUND In the setting of kidney transplantation, cinacalcet has been given, mainly, once daily, but also twice daily. The aims of this prospective study were to assess the acute pharmacodynamic effect of cinacalcet administrated once or twice daily to kidney transplant patients with normal renal function and persisting hypercalcaemia due to hyperparathyroidism and to evaluate 1-year efficacy and tolerance of cinacalcet given at a dose of 30 mg b.i.d. METHODS Eleven patients, who received a transplant 6 (6-59) months previously, were included in the study. A first kinetic was done after administration of 60 mg of cinacalcet at 8 a.m. After a washout period of 1 week, the second kinetic was performed with cinacalcet given at 30 mg b.i.d within a 12-h period. RESULTS During both kinetics, serum calcium (sCa), ionized calcium (sCa(2+)), albumin-corrected Ca and parathyroid hormone (PTH) levels decreased significantly. At 24 h after the second kinetic, sCa(2+) was significantly lower. After 1 year of cinacalcet treatment, given at the dose of 30 mg b.i.d., there was a significant decrease in sCa, sCa(2+), PTH levels and calcium x phosphorus (Ph) product. In contrast, Ph levels increased significantly. There was no significant change in renal function. CONCLUSION Once- or twice-daily acute administration of cinacalcet to kidney-transplant patients has similar efficacy. One-year administration of cinacalcet, given as two daily doses, is safe and efficient.

Long-term Prospective Population PK Study in GIST Patients—Letter

The study conducted by Eechoute and colleagues ([1][1]) revealed additional and useful information regarding imatinib pharmacokinetics. By accumulating plasma imatinib concentrations in 50 patients for 12 months, they observed significantly lower concentrations after 90 days of treatment. It was

Polyoma BK virus-associated nephropathy in kidney-transplant patients: effects of leflunomide on T-cell functions and disease outcome.

BACKGROUND In kidney-transplant recipients, leflunomide has been shown to be efficient for treating polyomavirus BK virus-associated-nephropathy (PVAN). However, it is unknown whether the beneficial effect of leflunomide is related to it having a lower immunosuppressive effect than mycophenolate mofetil (MMF), or to its anti-viral activity. The aim of this study was to assess i) T-cell functions before and after conversion from MMF to leflunomide in kidney-transplant patients with PVAN, and ii) effects of leflunomide on PVAN outcome. PATIENTS AND METHODS Twelve patients were enrolled in this study. At PVAN diagnosis, MMF was replaced by leflunomide. Other immunosuppressive drug doses and levels were maintained unchanged. T-cell functions, i.e., intralymphocyte cytokine expression (IL-2 and TNF-alpha), T-cell activation [i.e., transferrin receptor (CD71) and interleukin (IL)-2 alpha-chain (CD25) expression], and T-cell proliferation were measured using a flow-cytometry whole-blood assay before and at one month after conversion. RESULTS Despite a slight decrease in tacrolimus trough levels, no significant change in T-cell-function biomarkers was observed after conversion. After a follow-up of 6 (4-30) months, five patients were cleared of the virus, and decreased viral load was observed in four patients. Only one patient suffered a graft loss. No difference in immunological parameters was observed between patients who were cleared or not of BKV. CONCLUSION Results of this pilot study suggest that the potential benefits of leflunomide to treat PVAN in kidney-transplant patients is not related to reduced immunosuppression induced by replacing MMF by leflunomide. Virological studies are required to determine the anti-BKV effect of leflunomide.

Mycophenolic Acid Pharmacokinetics and Relapse in Children with Steroid–Dependent Idiopathic Nephrotic Syndrome

BACKGROUND AND OBJECTIVES Therapeutic drug monitoring of mycophenolic acid can improve clinical outcome in organ transplantation and lupus, but data are scarce in idiopathic nephrotic syndrome. The aim of our study was to investigate whether mycophenolic acid pharmacokinetics are associated with disease control in children receiving mycophenolate mofetil for the treatment of steroid-dependent nephrotic syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a retrospective multicenter study including 95 children with steroid-dependent nephrotic syndrome treated with mycophenolate mofetil with or without steroids. Area under the concentration-time curve of mycophenolic acid was determined in all children on the basis of sampling times at 20, 60, and 180 minutes postdose, using Bayesian estimation. The association between a threshold value of the area under the concentration-time curve of mycophenolic acid and the relapse rate was assessed using a negative binomial model. RESULTS In total, 140 areas under the concentration-time curve of mycophenolic acid were analyzed. The findings indicate individual dose adaptation in 53 patients (38%) to achieve an area under the concentration-time curve target of 30-60 mg·h/L. In a multivariable negative binomial model including sex, age at disease onset, time to start of mycophenolate mofetil, previous immunomodulatory treatment, and concomitant prednisone dose, a level of area under the concentration-time curve of mycophenolic acid >45 mg·h/L was significantly associated with a lower relapse rate (rate ratio, 0.65; 95% confidence interval, 0.46 to 0.89; P=0.01). CONCLUSIONS Therapeutic drug monitoring leading to individualized dosing may improve the efficacy of mycophenolate mofetil in steroid-dependent nephrotic syndrome. Additional prospective studies are warranted to determine the optimal target for area under the concentration-time curve of mycophenolic acid in this population.

A candidate gene approach of the calcineurin pathway to identify variants associated with clinical outcomes in renal transplantation

AIM To investigate the potential influence of variants in genes involved in the calcineurin pathway on the efficacy and toxicity of calcineurin inhibitors in renal transplantation. MATERIALS & METHODS Twenty-three polymorphisms in thirteen genes were tested in 381 renal transplant recipients receiving ciclosporin (n = 221) or tacrolimus (n = 160) and mycophenolate mofetil. Data were collected prospectively over the first year post-transplantation. RESULTS Multivariate survival analyses revealed no genetic associations with biopsy proven acute graft rejection and serious infections. Donor-recipient Cytomegalovirus mismatch was the only variable associated with serious infection. CONCLUSION This large exploratory study casts doubts on the potential interest of genetic biomarkers related to CNI pharmacodynamics but associations with other phenotypes in transplantation deserve further studies.

Mycophenolic acid 12-hour area under the curve in de novo liver transplant patients given mycophenolate mofetil at fixed versus concentration-controlled doses.

Therapeutic drug monitoring of mycophenolate mofetil (MMF) was found to be beneficial in preventing acute rejection after kidney transplantation. The aim of this pilot prospective study was to evaluate the efficacy of MMF dose adjustment in de novo liver transplant patients receiving MMF at fixed versus concentration-controlled doses [ie, adapted to mycophenolic acid (MPA) AUC0-12h] and tacrolimus during the first 12 months posttransplant. Twenty-nine patients received steroids only up to day 10, induction therapy by lymphoglobulins followed by tacrolimus and MMF. In all patients, MPA AUC0-12h were measured on posttransplant days 7 and 14 and at months 1, 2, 3, 6, and 12. From March 2006 to March 2007, 15 patients received MMF at a fixed dose of 1 g twice a day for 12 months. From April 2007 to December 2007, MMF was given to 14 patients at a dose of 1 g twice a day until day 7 and was then adapted to reach an MPA AUC0-12h target of 30-60 mg·h/L. The proportion of MPA AUC0-12h values within the target range was similar in both groups. The proportion of patients with MPA AUC0-12h below 30 mg·h/L tended to be higher in the fixed dose group within the first month posttransplant. However, MMF dose did not differ significantly between the 2 groups at any period except month 1. MPA AUC0-12h tended to be higher in the concentration-controlled group at day 14 and month 2 and was significantly so at month 1. Tacrolimus trough concentrations tended to be lower in the concentration-controlled group at all study periods and was significantly so at month 3. At 12 months posttransplant, patient and graft survivals, acute rejection rate, and adverse events were similar in both groups. We concluded that adapting the dose of MMF resulted in a significant increase in MPA AUC0-12h at month 1. There was a trend toward a lower proportion of patients with MPA AUC0-12h below 30 mg·h/L in the concentration-controlled group. No difference in outcome was found between both groups.

Antiretroviral unbound concentration during pregnancy: piece of interest in the puzzle?

Atazanavir and darunavir total concentrations (drug bound to plasma proteins plus unbound drug) progressively decrease during pregnancy. This pharmacokinetic variation leads physicians to recommend increasing doses. Conversely, the unbound concentration (Cu), i.e. the pharmacologically active form of the drug, remains unchanged. The explanation of this desynchronization lies in the fact that the clearance of the unbound form, corresponding to the intrinsic metabolic capacity of the hepatocytes, is the only factor driving Cu, and is constant during pregnancy. The attention of HIV physicians should be attracted to this aspect of pharmacokinetics, which is often incompletely understood and could lead to inadequate dose adjustment, which could then cause overexposure of the foetus for many months, with unknown consequences.

Comparison of the exposure of mycophenolate mofetil and enteric-coated mycophenolate sodium in recipients of kidney-pancreas transplantation

BACKGROUND Patients with a simultaneous pancreas-kidney transplant (SPKT), especially those with gastroparesis, often have gastro-intestinal (GI) disorders that can modify immunosuppressant pharmacokinetics. We compared the MPA 12-hours area under the curve (AUC(0-12)) in SKPT patients with severe gastroparesis receiving mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS). MATERIAL/METHODS Fifteen SKPT patients having a severe gastroparesis were switched, at 182 (69-1523) days post-transplantation, from MMF to EC-MPS because of GI disorders. MPA AUC(0-12) values were obtained before and after the switch, ie, under MMF (500 mg b.i.d.) at 169 (51-1522) days post-transplantation and EC-MPS (360 mg b.i.d.) at 102 (26-355) days after the switch. RESULTS Mean MPA AUC(0-12) h did not differ significantly under MMF and EC-MPS, ie, 40.13±14 and 38.24±15.5 mg*h/L, respectively. Trough and maximal MPA concentrations were similar with both MPA formulations. Although all patients had GI disorders under MMF (100%), only 3 had persistent GI disorders under EC-MPS (20%) (p<0.001). CONCLUSIONS In SKPT patients with severe gastroparesis, exposure to MPA is similar under MMF and EC-MPS. However, the incidence of GI disorders is significantly lower when patients are given EC-MPS.