Higher Doses Of Mycophenolate Mofetil Research Articles

Dose effects of mycophenolate mofetil in Chinese patients with neuromyelitis optica spectrum disorders: a case series study

BackgroundNeuromyelitis optica (NMO) spectrum disorder (NMOSD) is a devastating autoimmune inflammatory disorder of the central nervous system, which can result in blindness or paralysis. Currently, there is a dire need for new treatment options in the clinic. Several case series have shown that mycophenolate mofetil (MMF) may be an effective treatment for NMOSD patients. The dosing of MMF in the treatment of NMOSD has been poorly studied. Therefore, we evaluated the efficacy, tolerability, influential factors and optimal dosage of MMF in Chinese patients with NMOSD.MethodsA case series of 109 NMO or NMOSD (limited forms of NMO with seropositive AQP4-IgG) patients were retrospectively analyzed and followed up. Out of the 109 patients, 86 patients had received MMF for 6 months or longer and were included for efficacy assessment.ResultsWhen comparing the annualized relapse rate (ARR) of MMF treatment with that of pre-MMF treatment period, MMF was found to significantly reduce ARR in 75 (87%) patients (p < 0.0001). The median pre-treatment Expanded Disability Status Scale (EDSS) score in remission decreased from 3 (range, 0–8.5) to 2.5 (range, 0–8) at the last follow-up (p = 0.006), yet no significant difference was found in the visual score. The higher doses of MMF (1750 mg/d to 2000 mg/d) significantly lowered the relapse risks compared with lower doses (1000 mg/d or less, p < 0.0001) or moderate doses (1250 to 1500 mg/d, p = 0.031). Coexisting with systemic autoimmune diseases (HR, 2.418; p = 0.0345) and attack number before MMF initiation (HR, 1.117; p = 0.02) were important risk factors for relapses. MMF was generally well tolerated with adverse effects occurring in 21 patients (19%). While four patients decreased their daily doses because of the adverse effects, only one patient stopped MMF treatment.ConclusionsMMF is generally effective and well tolerated in Chinese NMOSD patients. High-dose MMF was more potent than the lower dose for NMOSD patients, with 1750 mg of daily MMF being the recommended dosage for Chinese patients with NMOSD. MMF treatment reduces the frequency of relapses and improves the quality of life for patients with this debilitating disease.

Successful Cost-Effective Prevention of Cytomegalovirus Disease in Kidney Transplant Recipients Using Low-Dose Valganciclovir.

Low-dose valganciclovir prophylaxis is still under investigation in renal transplant procedures. Our aim was to assess the cost effectiveness of 450 mg versus 900 mg valganciclovir prophylaxis in kidney transplant recipients. In this prospective trial, 201 kidney transplant patients were randomized (1:1) to receive 450 mg/d (group 1, n = 100) or 900 mg/d (group 2, n = 101) valganciclovir prophylaxis for the first 6 months after transplant. Patients were studied for incidence of cytomegalovirus disease, leucopenia episodes, rejection episodes, and graft outcomes along with associated costs over 1 year. Costs (in US dollars) of treatment of rejection were also analyzed. Demographic features of the studied groups were comparable. We found that the cost of cytomegalovirus care in group 1 patients was significantly lower (by 50% at 6 months; P < .001), with less leukopenia episodes (P = .04), lower doses of granulocyte colony-stimulating factor (by 30% at 6 months; P = .03), higher doses of mycophenolate mofetil (P = .04), and less rejection episodes (P = .01) compared with group 2. In group 2, there were more episodes of cytomegalovirus infection (P = .052) and BK virus nephropathy (P = .04). Graft and patient outcomes were satisfactory in both groups. Low-dose valganciclovir for cytomegalovirus prophylaxis after renal transplant is safer, effective and without breakthrough infection, and less costly than using the usual dose.

Higher Dose of Mycophenolate Mofetil Reduces Acute Graft-versus-Host Disease in Reduced-Intensity Conditioning Double Umbilical Cord Blood Transplantation

Mycophenolate mofetil (MMF) is frequently used in hematopoietic cell transplantation (HCT) for graft-versus-host disease (GVHD) prophylaxis and to facilitate engraftment. We previously reported that a higher level of mycophenolic acid can be achieved with an MMF dose of 3 g/day than with 2 g/day. Here, we retrospectively compared clinical outcomes of reduced-intensity conditioning (RIC) double umbilical cord blood (dUCB) HCT recipients receiving cyclosporine A with MMF 2 g (n = 93) versus 3 g (n = 175) daily. Multiple regression analysis adjusted for antithymocyte globulin in the conditioning revealed that MMF 3 g/day led to a 49% relative risk (RR) reduction in grade II to IV acute GVHD rate (RR, .51; 95% confidence interval, .36 to .72; P < .01). However, the higher MMF dose was not protective for chronic GVHD. Additionally, MMF dose was not an independent predictor of neutrophil engraftment or treatment-related mortality at 6 months or 2-year post-transplantation disease relapse, disease-free survival, or overall survival. Higher MMF dose did not increase risk of infectious complications, and infection-related mortality was similar for both MMF doses. Our data indicate that MMF 3 g/day reduces the risk of acute GVHD without affecting other clinical outcomes and should be used for GVHD prophylaxis after RIC dUCB transplantation.

Effect of Immunosuppression on T-Helper 2 and B-Cell Responses to Influenza Vaccination.

Influenza vaccine immunogenicity is suboptimal in immunocompromised patients. However, there are limited data on the interplay of T- and B- cell responses to vaccination with simultaneous immunosuppression. We collected peripheral blood mononuclear cells from transplant recipients before and 1 month after seasonal influenza vaccination. Before and after vaccination, H1N1-specific T- and B-cell activation were quantified with flow cytometry. We also developed a mathematical model using T- and B-cell markers and mycophenolate mofetil (MMF) dosage. In the 47 patients analyzed, seroconversion to H1N1 antigen was demonstrated in 34%. H1N1-specific interleukin 4 (IL-4)-producing CD4(+) T-cell frequencies increased significantly after vaccination in 53% of patients. Prevaccine expression of H1N1-induced HLA-DR and CD86 on B cells was high in patients who seroconverted. Seroconversion against H1N1 was strongly associated with HLA-DR expression on B cells, which was dependent on the increase between prevaccine and postvaccine H1N1-specific IL-4(+)CD4(+) T cells (R(2) = 0.35). High doses of MMF (≥ 2 g/d) led to lower seroconversion rates, smaller increase in H1N1-specific IL-4(+)CD4(+) T cells, and reduced HLA-DR expression on B cells. The mathematical model incorporating a MMF-inhibited positive feedback loop between H1N1-specific IL-4(+)CD4(+) T cells and HLA-DR expression on B cells captured seroconversion with high specificity. Seroconversion is associated with influenza-specific T-helper 2 and B-cell activation and seems to be modulated by MMF.

The Optimal MMF Dose in Tacrolimus Treated Patients

To the Editor: We appreciate the opportunity to respond to the Letter to the Editor of Knotek et al (1Knotek M Galešić Ljubanović D Mihovilović K Maksimović B Tacrolimus or mycophenolate in kidney transplantation—Less, or more?.Am J Transplant. 2014; 14: 1220Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). In their letter they propose a novel immunosuppressive strategy, aimed at treating de novo kidney transplant recipients with (very) low-dose tacrolimus and a higher mycophenolate mofetil (MMF) dose. The hypothesis of their prospective study is that reduced exposure to tacrolimus will result in an improved histology in 1-year protocol biopsies (less interstitial fibrosis and tubular atrophy), while the higher MMF dose (3 g daily) compensates for the lower tacrolimus exposure and will maintain efficacy. We feel that the observations in our analysis of three large, randomized-controlled trials (2Bouamar R Shuker N Hesselink DA et al.Tacrolimus predose concentrations do not predict the risk of acute rejection after renal transplantation: A pooled analysis from three randomized-controlled clinical trials.Am J Transplant. 2013; 13: 1253-1261Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar) suggest that the currently targeted tacrolimus predose concentrations may be too high and that a further reduction of the target levels is possible without compromising efficacy. We agree that optimizing MMF exposure is likely to further improve the outcome. What the optimal MMF dose would be has been a matter of debate for some time. In the registration trials, MMF doses of 2 or 3 g per day were compared with placebo or azathioprine treatment. Patients in these studies were on full-dose cyclosporine (CsA) treatment. It may well be that in a setting of low-dose tacrolimus treatment (say target predose concentrations in the range of 3 ng/mL) higher MMF doses would offer a benefit. It is known that in tacrolimus-treated patients an MMF dose of 2 g/day will result in mycophenolic acid (MPA) exposure below the target in 25% of patients in the first month after transplantation (and in CsA co-treated patients this occurs in no less than 50%). Temporary intensified dosing has been suggested to avoid reduced MPA exposure in the early posttransplant phase (3Gourishankar S Houde I Keown PA et al.The CLEAR study: A 5-day, 3-g loading dose of mycophenolate mofetil versus standard 2-g dosing in renal transplantation.Clin J Am Soc Nephrol. 2010; 5: 1282-1289Crossref PubMed Scopus (48) Google Scholar). Knotek et al (1Knotek M Galešić Ljubanović D Mihovilović K Maksimović B Tacrolimus or mycophenolate in kidney transplantation—Less, or more?.Am J Transplant. 2014; 14: 1220Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar) propose a 3 g MMF dose in the first week, and in half of the patients this dose is maintained thereafter. Whether or not a prolonged duration of higher MMF dosing would offer a benefit when very low tacrolimus concentrations are targeted remains to be seen. One could expect more MMF-related toxicity in a substantial proportion of patients, as observed in an older MMF dose finding study in tacrolimus-treated patients (4Squifflet JP Bäckman L Claesson K et al.Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients.Transplantation. 2001; 72: 63-69Crossref PubMed Scopus (122) Google Scholar). Therapeutic drug monitoring for MPA may identify patients with over-exposure, and in such patients, dose reductions may improve tolerability to the proposed regimen (5van Gelder T Therapeutic drug monitoring for mycophenolic acid is value for (little) money.Clin Pharmacol Ther. 2011; 90: 203-204Crossref PubMed Scopus (15) Google Scholar). The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Dr. Hesselink has received lecture fees from Astellas Pharma. Dr. van Gelder has received lecture fees from Astellas Pharma, and Roche. Dr. Bernasconi has received consulting fees from F. Hoffmann-La Roche Ltd, Basel, Switzerland. All other authors have no conflicts to declare.

Mycophenolate mofetil maintenance therapy in renal transplant patients: long‐term results of the TranCept STAY study

This prospective observational study documented long-term renal function in transplant recipients receiving mycophenolate mofetil (MMF). Kidney allograft recipients>6 months post-transplantation, with a glomerular filtration rate (GFR)>20 mL/min, receiving MMF from time of transplantation were enrolled and followed for four yr. Subgroups were identified based on time between transplantation and enrollment: Y<1 (6 months-1 yr); Y1-2 (>1-2 yr); Y2-5 (>2-5 yr) and Y>5 (>5 yr). A total of 2040 patients were analyzed; 780, 410, 541 and 309 in subgroups Y<1, Y1-2, Y2-5 and Y>5. For all patients combined GFR decreased during the observational period by approximately 1 mL/min/yr (median GFR (mL/min) was 50.8, 50.5, 48.7, and 47.6 at one, two, three, and four yr). Survival estimates for decline in renal function (>20% GFR decline at one time point) were 78%, 66%, 57%, and 51% at one, two, three and four yr, with no significant differences between subgroups (p>0.05). In adult patients, higher doses of MMF (≥1 g/d) were associated with better GFR outcomes (median GFR (mL/min) 48.1 vs. 39.9 at four yr post-enrollment; p=0.0037). When comparing the effects of MMF combined with calcineurin inhibitors (CNIs), GFR was increased with lower doses of tacrolimus or cyclosporin. There were no major tolerability or acute rejection problems and graft survival was similar in all subgroups (graft survival estimates for all patients combined were 99%, 95%, 92%, and 90% at one, two, three, and four yr). Long-term MMF immunosuppression preserves renal function and higher MMF doses combined with lower CNI doses may provide better patient outcomes.

Pigmented villonodular synovitis of the hip in systemic lupus erythematosus: a case report

IntroductionPigmented villonodular synovitis is a rare disease of unknown etiology mostly affecting the knee and foot. Until now an association with autoimmune diseases has not been reported.Case presentationThe diagnosis of systemic lupus erythematosus was made in a 15-year-old Caucasian girl based on otherwise unexplained fatigue, arthralgia, tenosynovitis, leukopenia, low platelets and the presence of antinuclear and deoxyribonucleic antibodies. At the age of 20 a renal biopsy revealed lupus nephritis class IV and she went into complete remission with mycophenolate mofetil and steroids. She was kept on mycophenolate mofetil for maintenance therapy. At the age of 24 she experienced a flare-up of lupus nephritis with nephrotic syndrome and new onset of pain in her right hip. Magnetic resonance imaging, arthroscopy and subtotal synovectomy identified pigmented villonodular synovitis as the underlying diagnosis. Although her systemic lupus erythematosus went into remission with another course of steroids and higher doses of mycophenolate mofetil, the pigmented villonodular synovitis persisted and she had to undergo open synovectomy to control her symptoms.ConclusionSystemic lupus erythematosus is associated with many different musculoskeletal manifestations including synovitis and arthritis. Pigmented villonodular synovitis has not previously been reported in association with systemic lupus erythematosus, but as its etiology is still unknown, the present case raises the question about a causal relationship between systemic lupus erythematosus and pigmented villonodular synovitis.

Relationship of Tacrolimus Exposure and Mycophenolate Mofetil Dose With Renal Function After Renal Transplantation

The most common immunosuppressive treatment in de novo renal transplantation is a triple regimen that includes tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, and that may also include antibody induction. Whether nephrotoxicity is an issue with tacrolimus at the currently used dosages remains an open question. We pooled data from three large, randomized, de novo renal transplantation studies (Symphony, Fixed Dose Concentration Controlled [FDCC], and OptiCept) that used variations of the triple regimen with respect to tacrolimus target levels, MMF dosing, and antibody induction. We used multivariate linear regression to explore the relationship of renal function at 1 year after transplantation (estimated glomerular filtration rate) with tacrolimus levels and MMF dose measured over the previous 6 months. The model included also a series of possible confounders. RESULTS.: The analysis population consisted of 998 patients. On average, tacrolimus levels were in a range considered low (mean ± standard deviation 7.2 ± 2.54 ng/mL), and MMF dose was 1.5 ± 0.61 g/day. Lower tacrolimus levels and higher MMF doses were associated with significantly better renal function. There were other variables associated with renal function, most notably acute rejection, donor age, and delayed graft function. Subanalyses in each of the three studies gave a consistent picture. There was no overt difference in the effect sizes when patients with stage II (estimated glomerular filtration rate 60-89 mL/min) or stage III (30-59 mL/min) chronic kidney disease were assessed separately. Tacrolimus seems to have a moderate but consistent nephrotoxic effect even in modern efficient immunosuppressive regimens where it is used at lower doses than in previous years.

Mycophenolic Acid Predose Concentrations and Renal Function in a Mouse Model for Progressive Renal Fibrosis

Within the scope of this study, the potential antifibrotic effect of mycophenolate mofetil (MMF) on COL4A3-deficient mice as an animal model for progressive renal fibrosis was investigated regarding kidney function and survival. Thirty-five animals were randomly assigned to one of five groups and treated with doses of 0, 10, 50, 100, or 150 mg/kg MMF per day, respectively. When increasing somnolence was observed, indicating end-stage renal disease, the mice were euthanized and blood was obtained. Serum concentrations of creatinine, urea nitrogen, total protein, mycophenolic acid (MPA), and mycophenolic acid glucuronide (MPAG) were quantified. The kidney histology was examined using hematoxylin and eosin as well as trichrome staining. The mean overall survival was 65.9 (+/-6.1) days with no significant difference between the treatment groups (P > 0.05, Mantel-Cox test). Serum predose concentrations of MPA and MPAG showed considerable interindividual variability. There was no correlation between survival time and MPA or MPAG concentrations (P > 0.05, Spearman rank correlation). However, an apparent decrease in serum creatinine and urea nitrogen concentrations was observed at higher doses of MMF, eg, -54% for creatinine in the 150-mg/kg/day group compared with placebo. A highly significant reciprocal correlation between MPA concentrations and serum creatinine was demonstrated (P < 0.01, r = -0.655, Spearman rank correlation). In conclusion, MMF may be a candidate drug for preserving kidney function in progressive renal fibrosis.

Severe Relapsing Goodpasture's Disease Successfully Treated with Mycophenolate Mofetil

Goodpasture's disease is a rare autoimmune disorder characterised by the development of antiglomerular basement membrane autoantibodies, which typically presents with rapidly progressive crescentic glomerulonephritis and pulmonary haemorrhage. Even with aggressive nonspecific immunosuppression and plasma exchange, mortality remains high. We report a case of life-threatening Goodpasture's disease with relapsing pulmonary haemorrhage refractory to conventional therapy. Second line treatment was based on mycophenolate mofetil 1 g every 12 hours and prednisolone 60 mg/day. In this case, the use of a low-dose mycophenolate mofetil regimen turned out to be insufficient. However, in our opinion higher mycophenolate mofetil doses should be considered an alternative treatment, mainly in relapsing disease, due to its mechanism of action and current insufficient therapeutic weapons.

Explaining Variability in Mycophenolic Acid Exposure to Optimize Mycophenolate Mofetil Dosing

Large between- and within-patient variability has been observed in the pharmacokinetics of mycophenolic acid (MPA). However, conflicting results exist about the influence of patient characteristics that explain the variability in MPA exposure. This population pharmacokinetic meta-analysis of MPA in renal transplant recipients was performed to explore whether race, renal function, albumin level, delayed graft function, diabetes, and co-medication are determinants of total MPA exposure. A total of 13,346 MPA concentration-time data points from 468 renal transplant patients who participated in six clinical studies were combined and analyzed retrospectively. Sampling occasions ranged from day 1 after transplantation to 10 yr after transplantation. Concentration-time data were analyzed with nonlinear mixed-effect modeling. Exposure to total MPA, as determined by MPA clearance, significantly increased with increasing renal function, albumin level, and hemoglobin as well as decreasing cyclosporine predose level (P<0.001). These variables could explain 18% of the between-patient and 38% of the within-patient variability in MPA exposure. Differences in MPA exposure between patients with or without delayed graft function or between patients of different races are likely to be caused by the effect of renal function on MPA exposure. Diabetes did not have an effect on MPA exposure. The clinical implication is that a change in renal function or albumin level provides an indication for therapeutic drug monitoring as MPA exposure may be altered. Patients in whom cyclosporine and mycophenolate mofetil are combined may need higher mycophenolate mofetil doses, especially during the early phase after transplantation than currently recommended for optimal MPA exposure.

Impact of Mycophenolate Mofetil Loading on Drug Exposure in the Early Posttransplant Period

Achieving adequate therapeutic levels of immunosuppressive medications is important in rejection prevention. This study examined exposure to mycophenolic acid (MPA) in kidney transplant patients within the first 5 days posttransplantation. Methods This single-center, nonrandomized study of first solitary kidney allograft recipients receiving cyclosporine ( n = 116) or tacrolimus ( n = 50) included patients who received either 1 g or 1.5 g of mycophenolate mofetil twice daily starting postoperatively. Exposure to MPA was measured at days 3 and 5 posttransplant using published limited sampling time equations. Results There were no significant differences in exposure in the cyclosporine-treated patients receiving 3-g ( n = 22) compared to 2-g ( n = 94) daily doses (AUC [0–12] 33.8 ± 10.0 mg*h/L versus 30.1 ± 9.7 mg*h/L, P = .20, respectively). About half the patients in both groups had AUC [0–12] <30 mg*h/L on days 3 and 5 posttransplant. On the other hand, there was significantly greater exposure on day 3 in the tacrolimus-treated patients receiving 3 g ( n = 21) compared to 2 g ( n = 29) daily (AUC [0–12] 43.1 ± 9.0 mg*h/L versus 36.8 ± 11.1 mg*h/L, P = .016, respectively). On day 3 one (4.8%) patient receiving 3 g had an AUC [0–12] of <30 mg*h/L; whereas, eight (27.5%) receiving 2 g were below this level ( P = .068). The AUC [0–12] levels were not different on day 5. Conclusions Loading with higher doses of mycophenolate mofetil results in greater exposure and a trend toward more patients in the therapeutic window within the first week for tacrolimus- but not for cyclosporine-treated patients.

Equivalent Pharmacokinetics of Mycophenolate Mofetil in African-American and Caucasian Male and Female Stable Renal Allograft Recipients

African-American (AA) renal transplant recipients require higher doses of mycophenolate mofetil (MMF) than Caucasians. A hypothesized pharmacokinetic (PK) difference was tested in stable renal transplant recipients. Whole blood was collected before, and 20, 40 and 75 min, and 2, 3, 4, 6, 8 and 12 h after the MMF dose. Mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) were analyzed using HPLC. Analysis of variance was performed for the primary end-points of dose-adjusted PK parameters AUC0–12 and Cmax of MPA using log-transformed values. Differences between races and genders were estimated: 90% confidence intervals (CI) were calculated. Back-transformation gave estimates of the race and gender ratio and their CI. Equivalence of the groups was determined if the 90% confidence limits were included in the interval (0.80, 1.25). The calculated PK parameters were comparable among the four subgroups (Caucasian, AA, Male, Female). The 90% CIs for the ratio of dose-adjusted AUC0–12 of MPA between races were between 89.7 and 112.9%. There were no race, gender or race-by-gender effects (p-values = 0.196) nor differences between diabetics and nondiabetics. This study demonstrates that dosing requirement for MMF in AA and Caucasians is unlikely to be related to different exposures to MPA.

Cryopreservation and mycophenolate therapy are detrimental to hematopoietic progenitor cells.

The aim of the present study was to determine whether certain components of nonmyeloablative regimens for hematopoietic cell transplantation might compromise the growth of hematopoietic progenitors. Porcine peripheral blood progenitor cells (PBPC) were cytokine-mobilized, collected by leukapheresis, and cryopreserved using 5% dimethyl sulfoxide and 6% hydroxyethyl starch. The influence of cryopreservation on PBPC was tested in vitro by enumeration of colony-forming units (CFUs) in methylcellulose and cobblestone area-forming cell (CAFC) subsets in stromal-associated long-term cultures on fresh and frozen PBPC. The effects of mycophenolate mofetil (MMF) on porcine PBPC and baboon and human bone marrow (BM) were tested in vitro by adding varying doses of MMF to the CFU assays. One baboon was treated with increasing doses of MMF (100-500 mg/kg per day continuously intravenous), and sequential BM aspirations were tested for CFU content. Fresh cytokine-mobilized PBPC had similar frequencies of progenitor cells when compared with porcine BM. Freezing-thawing of PBPC had no effect on porcine CFUs but reduced the recovery of CAFCs by more than 90%. In vitro, MMF completely inhibited the development of porcine and human CFUs at a concentration of 1 microg/mL and of baboon CFUs at levels between 10 and 100 microg/mL. Plasma-free mycophenolic acid levels of 10 to 30 microg/mL were associated with decreased CFUs in the BM. Cryopreservation and MMF potentially prevent engraftment of porcine PBPC by reducing the content or development of progenitor cells. These results indicate that the use of fresh PBPC might improve the induction of mixed hematopoietic chimerism and raise the possibility that use of high doses of MMF in the poststem cell transplant may compromise engraftment.

The impact of novel immunosuppressive agents on infections in organ transplant recipients and the interactions of these agents with antimicrobials.

Several of the new immunosuppressive agents that are used to treat transplant recipients possess in vitro activity against specific pathogens, enhance the activity of antimicrobial agents, or have unique drug interactions with antimicrobial agents. Mycophenolate mofetil may have a protective effect against Pneumocystis carinii; it also enhances the activity of ganciclovir and has strong antiviral activity against human immunodeficiency virus type 1. High doses of mycophenolate mofetil have been associated with a higher frequency of tissue-invasive cytomegalovirus disease but not with asymptomatic cytomegalovirus infection. Rapamycin exhibits potent in vitro fungicidal activity against Cryptococcus neoformans and several pathogenic fungi in transplant recipients; however, it is not known whether its immunosuppressive effect in organ transplant recipients outweighs its antifungal activity. Recognition of the unique characteristics of these agents and the evolving spectrum of opportunistic infections has implications for the differential diagnosis, management, and prophylaxis of infections in organ transplant recipients in the modern immunosuppressive era.

Effects of mycophenolate mofetil in the development of systemic lupus erythematosus in (NZBxNZW)F1 mice

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) is a chronic and progressive autoimmune syndrome characterized by the production of multiple autoantibodies (autoAb) resulting in the generation of circulating immune complexes (IC). The deposition of these IC leads to the development of tissue lesions such as glomerulonephritis. The study of several strains of mice that spontaneously develop an autoimmune syndrome resembling human SLE have been of considerable value to analyze cellular and molecular mechanisms responsible for the development of the disease as well as to explore the efficiency of different therapies using immunesuppressive drugs. One of these new immunosuppressive agents, Mycophenolate Mofetil (MMF), have been used successfully to prevent SLE in several lupus-prone mice such as MRL.1pr and (NZBxNZW)F1 mice. However, the precise mechanism by which MMF modulates the development of SLE in these animals remains controversial. Whereas in some studies the therapeutic effect of MMF is secondary to the inhibition of autoAb production, in others the administration of MMF blocks the development of IC-mediated glomerulonephritis but not the production of autoAb. To gain insight into the mechanisms responsible for the therapeutic effect of MMF, in the present study (NZBxNZW)F1 female mice have been treated with either high or low doses of MMF from 3 months of age, when increased serum levels of anti-nuclear autoAbs are already present. MATERIAL AND METHODS

Mycophenolic acid levels in pediatric heart transplant recipients receiving mycophenolate mofetil

Background Mycophenolate mofetil (MMF) is an immunosuppressive agent that has shown promise in adult patients who have undergone heart transplantation. There have been a number of studies of the pharmacokinetics of MMF in adult solid organ transplant recipients, but there is very little information in the pediatric population. The purpose of this study was to review our experience with MMF dosing and the role of mycophenolic acid (MPA) levels for therapeutic drug monitoring in a population of pediatric heart transplant recipients. Methods Data were obtained by review of the pediatric heart transplant database between November 1, 1997 and October 15, 1998. The data included all serum trough MPA levels, patient age, weight, height, indication for and dose of MMF, other medications, and details of all episodes of graft rejection. Results Forty-four patients (27 males) had a total of 128 serum trough MPA levels. Median age at transplant was 2.7 years (7 days to 18.4 years), and at time of review was 6.3 years (29 days to 23.5 years). MMF treatment was used for induction in 18 patients, induction and rejection in 23 patients and graft vasculopathy in 3 patients. Dosing by body surface area (mg/m 2), age and interval from transplantation were all independently associated with MPA level. There was a trend toward requiring higher doses to achieve desired levels (>3 ng/ml) in younger patients. The average dose to achieve desired levels was higher in the immediate post-transplant period. There was a trend that MPA levels for a given dose were higher in patients on concurrent tacrolimus therapy. Conclusions (1) There is marked individual variation in pharmacokinetics of MMF in pediatric patients; (2) dosing by body surface area may be advantageous; (3) higher MMF doses may be required at younger ages and in the early period after transplantation; (4) lower MMF doses may be required with concurrent tacrolimus therapy; and (5) serum trough MPA levels may relate to efficacy. Therefore, therapeutic drug monitoring of serum trough MPA levels may be required for individualized MMF dosing in pediatric cases.

MYCOPHENOLIC ACID (MPA) LEVELS IN PEDIATRIC HEART TRANSPLANT RECIPIENTS RECEIVING MYCOPHENOLATE MOFETIL

472 Mycophenolate mofetil (MMF) is an immunosuppressive agent that has shown promise in adult patients who have undergone heart transplantation. There have been a number of studies of the pharmacokinetics of MMF in adult solid organ transplant recipients, but there is very little information in the pediatric population. Purpose: To review our experience with MMF dosing and the role of MPA levels for therapeutic drug monitoring in a population of pediatric heart transplant recipients. Data was obtained by review of the pediatric heart transplant database between Nov. 1, 1997 and Oct. 15, 1998. The data included all serum trough MPA levels, patient age, weight, height, indication for and dose of MMF, other medications, and details of all episodes of graft rejection. Forty-four patients (27 males) had a total of 127 serum trough MPA levels. Median age at transplant was 2.7 yrs (0.02 to 18.4 yrs), and at time of review was 6.3 yrs (0.08 to 23.5 yrs). MMF treatment was used for induction in 18 patients, induction and rejection in 23 patients, and graft vasculopathy in 3 patients. Results: There was marked intraindividual (coefficient of variation 6.3-65%) and interindividual variation in MPA level with dosing by weight (R=0.19) and by body surface area (R=0.07), making it difficult to predict the level for any given dose of MMF. There was a significant trend to requiring higher doses to acheive therapeutic drug levels (3-7 ng/mL) in patients less than 5 years of age (125±29 mg/kg for age 0-1 yrs, 101±51 mg/kg for age 1-5 yrs, 49±17 mg/kg for >16 yrs; ANOVA p<0.01). The average dose to acheive therapeutic levels was higher in the immediate post-transplant period (4-8 wks post-transplant, 109±29 mg/kg) than at any time >8 weeks post-transplant (59±34 mg/kg; p<0.001). There were no therapeutic levels at <1 week post-transplant at a similar dose that resulted in therapeutic levels at > 8 weeks post-transplant. There was a trend that MPA levels for a given dose were higher in patients on concurrent FK506 therapy. Conclusions: 1) There is marked intra- and interindividual variation in pharmacokinetics of MMF in pediatric patients, 2) higher MMF doses are required at younger ages and in the early period post-transplant, and 3) lower MMF doses may be required with concurrent FK506 therapy. Therefore, therapeutic drug monitoring of serum trough MPA levels is required for individualization of MMF dosing in pediatrics.