Pharmacokinetics of enteric-coated mycophenolate sodium in stable pediatric renal transplant recipients

This study aims to characterize the pharmacokinetics of mycophenolic acid (MPA) and its glucuronide metabolite (mycophenolic acid 7-O-glucuronide, MPAG) following single oral administration of enteric-coated mycophenolate sodium (EC-MPS, myfortic) at an approximate dose level of 450 mg/m(2) body surface area (BSA) to 25 stable renal transplant recipients (aged 5-16 yr), and to evaluate the safety and tolerability of EC-MPS in this pediatric population. Patients had been maintained on a cyclosporine emulsion, Neoral-based immunosuppressive regimen for at least 3 months and had received their first or second renal transplant more than 6 months prior to entry into the study. After a brief lag phase (t(lag) 0.75 h), MPA was rapidly absorbed (t(max) 2.5 h) and rapidly converted to MPAG (t(max) 3.25 h), with relatively high plasma concentrations of MPAG (C(max) 67.7 microg/mL) compared with MPA (C(max) 36.3 microg/mL). The elimination half-life for MPAG was slightly longer than for MPA (approximately 13 h vs. 8.5 h), and the apparent oral clearance of MPA was approximately 0.2 L/h/kg. The pharmacokinetics of MPA or MPAG were not affected by age, body weight or BSA, within the study population. The pharmacokinetic results for pediatric patients are comparable with those obtained previously in adults, although exposure based on AUC(0-infinity) was approximately 23% higher, and this finding may be a result of dosing on the basis of BSA, rather than body weight. The recommended dose of EC-MPS in pediatric patients is 400-450 mg/m(2) twice daily or, alternatively, approximately 10-14 mg/kg twice daily when used in combination with cyclosporine microemulsion.     

Benefits of conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in pediatric renal transplant patients with stable graft function

Abstract:  Conversion from MMF to EC-MPS may reduce GI complications and permit increased MPA dosing with a concomitant reduction in CNI dose. In a prospective trial, paediatric renal transplant patients with stable graft function were converted from MMF to EC-MPS and followed-up for 12 months. Data from 28 patients (mean age 13.9 ± 3.1 yr) were available for analysis. Mean EC-MPS dose increased significantly from conversion to month 12 (668 ± 81 mg/m²/day vs. 747 ± 98 mg/m²/day, p < 0.001). CsA-ME dose (n = 23) decreased from 5.3 ± 1.7 mg/kg/day at conversion to 4.6 ± 1.4 mg/kg/day at month 12 (p = 0.010). cGFR increased from 69.5 ± 23.3 mL/min/1.73 m² at the time of conversion to 80.7 ± 30.7 mL/min/1.73 m² at month 12 (p = 0.007). The number of patients reporting at least one GI event during six months prior to conversion was 15/28 (53.6%), declining to 8/28 (28.6%) at month 6 post-conversion and 5/28 (17.8%) at month 12. This single-arm study suggests that conversion of paediatric renal transplant patients from MMF to EC-MPS does not compromise efficacy and leads to improved GI tolerability. MPA dose increased and CsA-ME dose decreased significantly, with an associated improvement in calculated GFR. A large-scale controlled trial is required to confirm these promising findings.     

Improved gastrointestinal symptom burden after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in kidney transplanted children

Abstract:  It has been shown in adult kidney transplant recipients that a conversion from MMF to EC-MPS significantly reduced the GI related symptom burden. No such study exists on children with GI problems while receiving MMF therapy. Ten paediatric kidney transplant recipients (mean age 14.5 yr, s.d. 4.5) receiving triple immunosuppression (Cyclosporin A or Tacrolimus + MMF + Prednisolone) with severe GI symptoms were converted to an equimolar dose of EC-MPS. The GSRS was completed before and at four wk after the switch, and GFR was determined for a mean period of six months. Values were compared by the paired t-test. Mean GSRS improved significantly after the switch to EC-MPS in all but one patient, from 2.1 (s.d. 0.9) to 1.1 (s.d. 0.6). The differences could be found in all four subscales. Graft function did not change after conversion to EC-MPS. In children with moderate or severe GI symptoms while receiving MMF, conversion to EC-MPS led to significantly reduced GI symptoms.     

Pharmacokinetics and target attainment of mycophenolate in pediatric renal transplant patients

MPA is an immunosuppressive agent used to prevent graft rejection after renal transplantation. MPA shows considerable inter‐ and intraindividual variability in exposure in children and has a defined therapeutic window, and TDM is applied to individualize therapy. We aimed to study the exposure to MPA measured as the AUC in pediatric renal transplant patients, to identify factors influencing exposure and to assess target attainment. Children transplanted between 1998 and 2014 in a single center were included. Two groups were identified: Group 1 (AUC <3 wk post‐transplantation) and Group 2 (AUC >18 months post‐transplantation). Therapeutic targets were set at: AUC_0–12h of 30–60 mg h/L. A total of 39 children were included in Group 1 (median age 13.3 yr) vs. 14 in Group 2 (median age 13.4 yr). AUC_0–12h was 29.7 mg h/L in Group 1 and 56.6 mg h/L in Group 2, despite a lower dosage in Group 2 (584 and 426 mg/m², respectively). About 46% of patients reached the target AUC_0–12h in Group 1. Time since transplantation and serum creatinine were significantly associated with MPA exposure (p < 0.001), explaining 36% of the variability. Individualization of the mycophenolate dose by more intense and more early TDM could improve target attainment.     

Introduction of mycophenolate mofetil and cyclosporin reduction in children with chronic transplant nephropathy

Chronic transplant nephropathy (CTN) is the most important cause of kidney graft dysfunction. Studies in adult populations have reported a beneficial effect of non-nephrotoxic mycophenolate mofetil (MMF) on graft function in this setting. However, few studies were reported in children in this setting. We therefore reviewed the charts/medical records of renal transplanted patients < 18 yr of age at a single center who had switched from azathioprine to MMF as a result of progressive loss in graft function, for which vascular, infectious, and urological causes were excluded. Serum creatinine (SCr) and calculated creatinine clearance were compared prior to and after MMF introduction. Thirteen patients (nine male/four female), followed-up for 59.3 +/- 35.4 months after transplantation, were analyzed. Age at MMF introduction was 14.2 +/- 3.6 yr. In 11 patients a previous biopsy had shown features of CTN and four patients also presented signs of chronic cyclosporin A (CsA) nephrotoxicity. MMF was started at a dose of 1211 +/- 351 mg/day, and the CsA dose was decreased from 6.69 +/- 3.15 mg/kg/day 6 months before MMF to 4.8 +/- 2.3 mg/kg/day at the time of MMF introduction. CsA was withdrawn in four patients. The median (25-75%) SCr value increased from 1.60 mg/dL (range 1.3 to 1.87 mg/dL) 6 months before MMF to 2.2 mg/dL (range 1.87-2.32 mg/dL) when MMF was introduced. Six months after introduction of MMF, the SCr level had decreased to 1.5 mg/dL (range 1.2-1.8 mg/dL) and remained stable until the last follow-up (17.5 +/- 9.2 months after MMF was started). A similar pattern occured with calculated SCr clearance. There were no acute rejections after changes in immunosuppression. The safety of MMF was also analyzed and in only one patient was the drug stopped as a result of intractable diarrhea. These findings suggest that MMF is sufficiently powerful to allow a decrease/withdrawal of CsA without the burden of acute rejection in a pediatric population with CTN.     

Inosine 5′‐monophosphate dehydrogenase 1 haplotypes and association with mycophenolate mofetil gastrointestinal intolerance in pediatric heart transplant patients

Ohmann EL, Burckart GJ, Chen Y, Pravica V, Brooks MM, Zeevi A, Webber SA. Inosine 5′‐monophosphate dehydrogenase 1 haplotypes and association with mycophenolate mofetil gastrointestinal intolerance in pediatric heart transplant patients.
Pediatr Transplantation 2010: 14: 891–895. © 2010 John Wiley & Sons A/S. Abstract: MMF, the most commonly used adjuvant immunosuppressant in pediatric heart transplantation, has frequent GI adverse events. SNPs in inosine 5′‐monophosphate dehydrogenase I (IMPDH1) may contribute to MMF GI intolerance. Phased haplotypes may have more utility than individual SNPs in candidate gene association studies for complex traits. This study defined common IMPDH1 haplotypes and investigated whether these haplotypes influence MMF GI intolerance in 59 pediatric heart recipients. Genotypes were assessed by Taqman analysis of IMPDH1 rs2288553, rs2288549, rs2278293, rs2278294, and rs2228075, and haplotypes were inferred using Arlequin 3.01 software. GI intolerance was defined as diarrhea, vomiting, nausea, or abdominal pain requiring MMF dose holding for > 48 h or MMF discontinuation. GI intolerance occurred in 21 patients (35.6%). Ten IMPDH1 haplotypes were identified in this population. In univariable analyses, one haplotype was strongly associated with MMF GI intolerance with 59.1% of carriers of this haplotype experiencing MMF GI intolerance compared to 21.6% of non‐carriers (p = 0.005). In this study, we identify a common IMPDH1 haplotype associated with MMF GI intolerance in a population of pediatric heart transplant patients. This haplotype of interest did not demonstrate stronger association with MMF GI intolerance than an individual IMPDH1 SNP.     

Single-dose pharmacokinetics and tolerability of everolimus in stable pediatric renal transplant patients

Everolimus (Certican; RAD), a novel macrolide with potent immunosuppressive and anti-proliferative activities, prevents acute rejection in adult recipients of renal transplantation. This phase I trial conducted in stable pediatric renal transplant patients examined the single-dose pharmacokinetics, safety, and tolerability of everolimus in combination with cyclosporin A (CsA; Neoral) and corticosteroids, with or without azathioprine. Nineteen pediatric patients were enrolled and received a single 1.2 mg/m2 dose of everolimus. Everolimus was safe and well tolerated, with a low incidence of adverse events reported and none judged to be related to the study medication. Everolimus administration did not increase infection rates or produce clinically significant changes in vital signs or changes in electrocardiograms. Apparent clearance and volume of distribution of everolimus increased with age, weight, and body surface area in a generally linear manner across the pediatric demographic ranges. Compared with adults from a previous study, apparent clearance (L/h) and distribution volume (L) were lower in pediatric patients, whereas the elimination half-life was similar. Single-dose everolimus co-administration did not affect the steady-state pharmacokinetics of CsA. Based on this information, pediatric patients will need a dose scaled down for body size, but can probably maintain the same twice-daily dosing schedule used in adults.     

Use of prophylactic lamivudine and mycophenolate mofetil in renal transplant recipients with chronic hepatitis B infection

Chronic HBsAg carriers are known to have a higher risk of hepatitis-related mortality and morbidity when undergoing kidney transplantation. Immunosuppressants might flare up the infection that could be fulminating. Lamivudine and mycophenolate mofetil (MMF) have been shown to be effective in inhibiting replication of hepatitis B virus (HBV). With these two drugs, hepatitis related adverse outcome might be preventable when these patients are being transplanted. Four Chinese adolescents with chronic HBV infection were transplanted in our Department from 1999 to 2001. Immunosuppresants included prednisolone, cyclosporin A and MMF; azathioprine was not used for its potentially liver toxic effect. Prophylactic lamivudine 3 mg/kg and maximum 100 mg daily was given just before transplantation and was continued afterwards. HBV status and liver enzymes were monitored serially. Patients were followed up for 26.0 +/- 10.3 (11-34) months post-transplant and no mortality was reported. All grafts were functioning and no rejection was noted. MMF and lamivudine were well tolerated. Alanine transaminase was only transiently elevated in the first 2 months post-transplant in all patients and became normal afterwards. The patients were clinically well and liver function was normal at the last follow-up. However, HBV DNA became positive in three patients after the transplantation. YMDD mutant HBV was negative in one patient and undeterminable in the other three due to low virus load. In summary, with prophylactic lamivudine and MMF, short-term follow-up showed that renal transplant might be feasible and safe in chronic HBV carriers.     

Hyponatremia,hypo‐osmolality,and seizures in children early post‐kidney transplant

Post‐transplant seizures are uncommon in young kidney transplant recipients but can be harbingers of devastating outcomes such as cerebral edema and death. We reviewed all transplants performed at our institution from January 2013 to January 2014 and compared three patients who seized within 24 h post‐transplant (cases) with the remaining 33 transplant recipients (controls). Records were reviewed for hyponatremia, hypocalcemia, hypomagnesemia, BUN clearance, osmolality shifts, and blood pressure control in the first 24 h post‐transplant. All cases had more pronounced (p < 0.001) shifts in serum sodium and calculated serum osmolality, with their sodium decreasing by >15 mmol/L to nadir values of 124, 131, and 131 mmol/L, respectively. There were no differences in serum calcium corrected for hypoalbuminemia, serum magnesium, urine output, or blood pressure control between the groups. Our study suggests that mild hyponatremia and an acute decrease in serum osmolality are risk factors for potentially severe postoperative neurologic complications following kidney transplantation. Thus, peri‐transplant management should be optimized to anticipate and prevent these abnormalities.     

Prevalence of metabolic syndrome and obesity in renal transplanted Mexican children

Abstract:  The purpose of the study was to evaluate the prevalence of MS and obesity in Mexican children with more than one yr post-renal transplantation. Thirty-two children transplanted between January 2004 and February 2006 were included in the study. The weight and height at the time of renal transplant were obtained. A fasting blood sample was drawn for serum creatinine, adiponectin, and complete lipid profile, and a three-h glucose tolerance test was also taken. A complete nutritional evaluation was performed including anthropometry. There was a statistically significant increase in BMI at one yr post-transplant that was maintained at two yr post-transplant. Three patients exhibited obesity and were overweight. Seventeen patients had hypertension, 14 patients had low HDL, 12 patients had hypertriglyceridemia, all had normal fasting glucose, six of them had glucose intolerance, and two had waist circumference higher than 90%. Eight patients (25%) had MS. Patients with MS had higher proportion of deceased donor grafts, acute rejection episodes, and received more methylprednisolone pulses; also they had a statistically significant higher pretransplant BMI than patients without MS. There was a significant relationship between BMI at one yr post-renal transplant and creatinine clearance estimated by Schwartz formula.     

Use of belatacept to maintain adequate early immunosuppression in calcineurin‐mediated microangiopathic hemolysis post‐renal transplant

We report a 17‐yr‐old boy who developed a microangiopathic hemolytic anemia presumed secondary to tacrolimus shortly following a living‐related donor renal transplant. This was initially managed by plasmapheresis. Reinstitution of calcineurin inhibition using cyclosporine led to recurrence of hemolysis, so an alternative agent was needed. He was commenced on monthly intravenous belatacept, with no further recurrence of the hemolysis, and subsequent stable graft function. Modulation via CTLA‐4 offers an alternative immunosuppressive tactic if current regimens produce graft threatening adverse effects. The method of administration and frequency of dosage of belatacept also lends itself well to the high‐risk period of adolescence and transition. We propose that belatacept may therefore also have utility in difficult cases complicated by poor concordance, common in the adolescent age group.     

GCV/VCVG prophylaxis against CMV DNAemia in pediatric renal transplant patients: A systematic review and meta‐analysis

CMV disease continues to stand as a significant threat to the longevity of renal transplants in children. More pediatric recipients are CMV‐negative with CMV‐positive donor serologies resulting in a HR mismatch. The length of prophylaxis with GCV or VGCV required to optimally prevent recurrence of CMVDNAemia remains unknown. This study is a meta‐analysis comparing GCV/VGCV prophylaxis regimens provided for <6 months, from 6 to <12 months, and ≥12 months after transplant in order to prevent CMVDNAemia. The search conducted involved PubMed, EMBASE, ISI Web of Science, and Cochrane Central Register from inception through December 2017. Search terms Kidney Transplantation, CMV, GCV, and VGCV provided 204 studies for abstract review. Studies excluded were those which did not itemize pediatric data separately, single case reports, and duplicate studies. Pooled analysis of five retrospective studies and one prospective study identified that there is no statistically significant difference in the incidence of CMV DNAemia when comparing <6 months of prophylaxis and >12 months of prophylaxis (23% and 15%, respectively, P = 0.23). Regardless of the length of prophylaxis, there was no statistical difference in the incidence of CMV DNAemia in the HR patients (6 to <12 months vs <6 months, P = 0.62; 6 to <12 months vs ≥12 months, P = 0.78; ≥12 months vs <6 months, P = 0.83). This study identifies no optimal length of prophylaxis for HR mismatch pediatric renal transplant patients as many develop CMV DNAemia.     

Limited sampling strategy to predict the area under the curve of tacrolimus in Mexican renal transplant pediatric patients receiving Prograf® or non‐innovator formulations

TDM of tacrolimus is usually performed with trough levels (C_0h). However, in pediatric patients, C_0h may not be an adequate marker. The AUC is considered a more suitable indicator of drug exposure. As several blood samples are needed for the estimation of AUC, and LSS for predicting tacrolimus AUC and optimizing the dose adjustment have been proposed. Moreover, in emerging countries such as Mexico, non‐innovator formulations, which bioequivalence has not been demonstrated, are frequently used. Hence, the aim of this study was to develop and validate a LSS to predict the tacrolimus AUC_0‐12h in Mexican pediatric kidney transplant recipients who received either Prograf^® or non‐innovator tacrolimus formulations. A total of 56 pharmacokinetic profiles were randomized into two groups: model development (n = 28) and model validation (n = 28). The limited sampling equations were obtained after a stepwise multiple regression using AUC as the dependent variable and tacrolimus blood concentrations, quantified by CMIA, at different time points as the independent variables. The final equation included observed concentrations at 1 hour (C_1h) and 4 hours (C_4h) after dose administration. The predictive performance of the model was adequate in terms of both, bias and precision. Results strongly suggest that the clinical use of this LSS could provide an ethical, cost‐, and time‐effective method in the TDM of tacrolimus in pediatric patients with kidney transplant. The model proved to be adequate with either Prograf^® or non‐innovator tacrolimus formulations of dubious bioequivalence.     

Three‐yr safety and efficacy of everolimus and low‐dose cyclosporine in de novo pediatric kidney transplant patients

The three yr results of a multicenter trial in de novo pediatric KT treated with a proliferative signal inhibitor and low dose CNI are presented. Thirty‐seven children (9.1 ± 5 yr old) received basiliximab, cyclosporine A (CyA C2:1400 ng/mL), (MMF C0:1.5–3 μg/mL), and prednisone. Three wk later everolimus was started (C0:5–10 ng/mL), CyA was reduced (C2:600 ng/mL after 90 days 300 ng/mL), and MMF discontinued. During the three‐yr period patient and graft survivals were 96%. One patient died for causes unrelated to the immunosuppression. Cumulative acute rejection rate including protocol and indication biopsies was 21.9%. None of the patients had signs of chronic humoral rejection. Incidence of dnDSA was 5%, 11%, and 22% at one, two, and three yr post‐transplant, respectively. Mean glomerular filtration rate measured at one yr and three yr post‐transplant was 105.5 ± 31 and 110.7 ± 27 mL/min/1.73 m², respectively. A growth velocity of 7.7 ± 6.7 cm/yr was achieved with positive catch‐up growth. No malignancy or post‐transplant lymphoproliferative diseases were diagnosed. In conclusion, the treatment based on basiliximab induction, everolimus, low‐dose cyclosporine, and low‐dose prednisone leads to good long‐term efficacy in de novo pediatric KT recipients.     

Evaluation of the current post‐transplantation Human Leukocyte Antigen antibody screening in pediatric renal transplant recipients

The necessity of post‐transplant monitoring for donor‐specific antibodies (DSAs) is unclear. This study evaluates the clinical relevance of post‐transplantation donor‐specific HLA antibodies in pediatric renal transplant recipients, aiming at better stratification of patients at risk of graft dysfunction and better recommendations for post‐transplant monitoring. A cohort of 68 pediatric kidney recipients, involving 76 transplantations between 2004 and 2014, was studied retrospectively. All patients were screened for HLA antibodies at 1, 3, 6, and 12 months after transplantation and yearly thereafter. Samples testing positive were further analyzed to detect DSA. A biopsy was performed on clinical indication. We studied the baseline characteristics of the patients with biopsy, with DSA, and with rejection. We assessed the effect of post‐transplant DSA on clinical outcome, including antibody‐mediated acute rejection and GFR decrease. In our cohort, the prevalence of DSA was 19% (13/68 transplantations). Most patients with HLA antibodies after transplantation were DSA‐positive (76%; 13/17). A clear association between DSA and subsequent rejection was found. At the end of the study period, a significantly lower GFR was found in patients with biopsy, DSA, or rejection. Based on our observations, we recommend routine post‐transplantation screening for HLA and DSA. The presence of DSA justifies a renal biopsy even in the absence of clinical signs of rejection.