Low-Dose Antithymocyte Globulin Has No Disadvantages to Standard Higher Dose in Pediatric Kidney Transplant Recipients: Report from the Pediatric Nephrology Research Consortium

Introduction Rabbit antithymocyte globulin (rATG) dosing strategies for induction in pediatric kidney transplantation vary between centers. It is not known whether a lower rATG induction dose provides safe and effective immunosuppression compared with a “standard” higher dose. Methods We performed a retrospective multicenter study of all isolated first-time kidney transplant recipients \u3c 21 years old who received rATG induction between 1 January 2010 and 31 December 2014 at 9 pediatric centers. An a priori cutoff of a 4.5-mg/kg cumulative rATG dose was used to identify low (≤ 4.5 mg/kg) and standard (\u3e 4.5 mg/kg) exposure groups. Outcomes examined included 12 months posttransplant graft function (estimated glomerular filtration rate [eGFR]); the occurrence of acute rejection, donor-specific antibody (DSA), neutropenia, and viral infection (cytomegalovirus [CMV], Epstein-Barr virus [EBV], and BK virus); and 24-month outcomes of posttransplant lymphoproliferative disorder (PTLD) occurrence and patient and graft survival. Results Two hundred thirty-five patients were included. Baseline features of the low and standard rATG dose groups were similar. By 12 months, the rATG dose group had no significant impact on the occurrence of neutropenia, positive DSA, or viral polymerase chain reaction (PCR). Graft function was similar. Acute rejection rates were similar at 17% (low dose) versus 19% (standard dose) (P = 0.13). By 24 months, graft survival (96.4% vs. 94.6%) and patient survival (100% vs. 99.3%) were similar between the low- and standard-dose groups (P = 0.54 and 0.46), whereas the occurrence of PTLD trended higher in the standard-dose group (0% vs. 2.6%, P = 0.07). Conclusion A low rATG induction dose ≤ 4.5 mg/kg provided safe and effective outcomes in this multicenter low immunologic risk pediatric cohort. Prospective studies are warranted to define the optimal rATG induction dose in pediatric kidney transplantation

The use of mycophenolate mofetil suspension in pediatric renal allograft recipients

Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adults after renal, cardiac, and liver transplantation. This study investigated the safety, tolerability, and pharmacokinetics of MMF suspension in pediatric renal allograft recipients. One hundred renal allograft recipients were enrolled into three age groups (33 patients, 3 months to <6 years; 34 patients, 6 to <12 years; 33 patients, 12 to 18 years). Patients received MMF 600 mg/m 2 b.i.d. concomitantly with cyclosporine and corticosteroids with or without antilymphocyte antibody induction. One year after transplantation, patient and graft survival (including death) were 98% and 93%, respectively. Twenty-five patients (25%) experienced a biopsy-proven (Banff grade borderline or higher) or presumptive acute rejection within the first 6 months post-transplantation. Analysis of pharmacokinetic parameters for mycophenolic acid (MPA) and mycophenolic acid glucuronide showed no clinically significant differences among the age groups. The dosing regimen of MMF 600 mg/m 2 b.i.d. achieved the targeted early post-transplantation MPA 12-h area under concentration-time curve (AUC 0–12 ) of 27.2 µg h per ml. Adverse events had similar frequencies among the age groups (with the exception of diarrhea, leukopenia, sepsis, and anemia, which were more frequent in the <6 years age group) and led to withdrawal of MMF in about 10% of patients. Administration of MMF 600 mg/m 2 b.i.d. is effective in prevention of acute rejection, provides predictable pharmacokinetics, and is associated with an acceptable safety profile in pediatric renal transplant recipients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42304/1/467-16-12-978_10160978.pd

Tacrolimus Population Pharmacokinetics in Paediatric Kidney Transplant Patients

Objectives: 1. To describe the pharmacokinetics (PK) of tacrolimus in paediatric kidney transplant recipients. 2. To determine the relationship between measures of tacrolimus exposure and renal function. 3. To determine if there were any differences in either the PK or pharmacodynamics (PD) of tacrolimus in brand versus generic formulations. Methods: Data from 1999-2014 were extracted from the electronic medical records from Intermountain Healthcare network. Data were available on 95 paediatric patients with kidney transplant taking oral tacrolimus. Reliable data was available in 77 patients. Using the individual predicted PK parameters from the population model several exposure metrics were derived for each dosing interval including; Cmin, Cmax and partial AUCs (2, 4, 6, 8, 10, 12h). We investigated the relationship between tacrolimus exposure and creatinine clearance in the first 30 days post-transplantation, using a simple slope-intercept model as well as an Emax model. Results: A total of 598 concentrations of tacrolimus were available for analysis. A one-compartment model described the final PK model, the significant covariates on clearance were haematocrit, body weight and post-transplant day. A total of 43 patients had data in the first 30 days post-transplant with a total of 470 creatinine concentrations available. The model that best described the relationship between tacrolimus exposure and creatinine clearance was an Emax model using a partial AUC of 4 hours. The significant covariates of this analysis were age, albumin, and formulation of the ED50 equivalent partial AUC 4h. The generic formulation (Sandoz) had a 35% increase partial AUC50 4h compared to the brand formulation. Conclusions: In the present work we developed a population PK model for tacrolimus in pediatric kidney transplant recipients the significant covariates have been previously identified [1]. We also determined an exposure-response relationship between tacrolimus and creatinine clearance. This relationship was influenced by patients age and albumin concentrations. Furthermore, we show that there is a difference in the pharmacodynamic effects of tacrolimus when comparing the brand formulation to the generic

Tacrolimus Population Pharmacokinetics in Paediatric Kidney Transplant Patients

Objectives: 1. To describe the pharmacokinetics (PK) of tacrolimus in paediatric kidney transplant recipients. 2. To determine the relationship between measures of tacrolimus exposure and renal function. 3. To determine if there were any differences in either the PK or pharmacodynamics (PD) of tacrolimus in brand versus generic formulations. Methods: Data from 1999-2014 were extracted from the electronic medical records from Intermountain Healthcare network. Data were available on 95 paediatric patients with kidney transplant taking oral tacrolimus. Reliable data was available in 77 patients. Using the individual predicted PK parameters from the population model several exposure metrics were derived for each dosing interval including; Cmin, Cmax and partial AUCs (2, 4, 6, 8, 10, 12h). We investigated the relationship between tacrolimus exposure and creatinine clearance in the first 30 days post-transplantation, using a simple slope-intercept model as well as an Emax model. Results: A total of 598 concentrations of tacrolimus were available for analysis. A one-compartment model described the final PK model, the significant covariates on clearance were haematocrit, body weight and post-transplant day. A total of 43 patients had data in the first 30 days post-transplant with a total of 470 creatinine concentrations available. The model that best described the relationship between tacrolimus exposure and creatinine clearance was an Emax model using a partial AUC of 4 hours. The significant covariates of this analysis were age, albumin, and formulation of the ED50 equivalent partial AUC 4h. The generic formulation (Sandoz) had a 35% increase partial AUC50 4h compared to the brand formulation. Conclusions: In the present work we developed a population PK model for tacrolimus in pediatric kidney transplant recipients the significant covariates have been previously identified [1]. We also determined an exposure-response relationship between tacrolimus and creatinine clearance. This relationship was influenced by patients age and albumin concentrations. Furthermore, we show that there is a difference in the pharmacodynamic effects of tacrolimus when comparing the brand formulation to the generic

Treatment Optimization of Maintenance Immunosuppressive Agents in Pediatric Renal Transplant Recipients

Graft survival in pediatric kidney transplant patients has increased significantly within the last three decades, correlating with the discovery and utilization of new immunosuppressants as well as improvements in patient care. Despite these developments in graft survival for patients, there is still improvement needed, particularly in long-term care in pediatric patients receiving grafts from deceased donor patients. Maintenance immunosuppressive therapies have narrow therapeutic indices and are associated with high inter-individual and intra-individual variability.Areas covered: In this review, we examine the impact of pharmacokinetic variability on renal transplantation and its association with age, genetic polymorphisms, drug-drug interactions, drug-disease interactions, renal insufficiency, route of administration, and branded versus generic drug formulation. Pharmacodynamics are outlined in terms of the mechanism of action for each immunosuppressant, potential adverse effects, and the utility of pharmacodynamic biomarkers.Expert opinion: Acquiring abetter quantitative understanding of immunosuppressant pharmacokinetics and pharmacodynamic components should help clinicians implement treatment regimens to maintain the balance between therapeutic efficacy and drug-related toxicity

Treatment Optimization of Maintenance Immunosuppressive Agents in Pediatric Renal Transplant Recipients

Graft survival in pediatric kidney transplant patients has increased significantly within the last three decades, correlating with the discovery and utilization of new immunosuppressants as well as improvements in patient care. Despite these developments in graft survival for patients, there is still improvement needed, particularly in long-term care in pediatric patients receiving grafts from deceased donor patients. Maintenance immunosuppressive therapies have narrow therapeutic indices and are associated with high inter-individual and intra-individual variability.Areas covered: In this review, we examine the impact of pharmacokinetic variability on renal transplantation and its association with age, genetic polymorphisms, drug-drug interactions, drug-disease interactions, renal insufficiency, route of administration, and branded versus generic drug formulation. Pharmacodynamics are outlined in terms of the mechanism of action for each immunosuppressant, potential adverse effects, and the utility of pharmacodynamic biomarkers.Expert opinion: Acquiring abetter quantitative understanding of immunosuppressant pharmacokinetics and pharmacodynamic components should help clinicians implement treatment regimens to maintain the balance between therapeutic efficacy and drug-related toxicity