J Am Soc Nephrol. 2021 Feb;32(2):502-516 doi: 10.1681/ASN.2020050645.
CET Conclusion
BACKGROUND:
Pharmacokinetic monitoring is insufficient to estimate the intensity of immunosuppression after transplantation. Virus-specific T cells correlate with both virus-specific and general cellular immune defense. Additional steering of immunosuppressive therapy by virus-specific T cell levels might optimize dosing of immunosuppressants. METHODS:In a multicenter, randomized, controlled trial, we randomized 64 pediatric kidney recipients to a control group with trough-level monitoring of immunosuppressants or to an intervention group with additional steering of immunosuppressive therapy by levels of virus-specific T cells (quantified by cytokine flow cytometry). Both groups received immunosuppression with cyclosporin A and everolimus in the same target range of trough levels. Primary end point was eGFR 2 years after transplantation. RESULTS:In the primary analysis, we detected no difference in eGFR for the intervention and control groups 2 years after transplantation, although baseline eGFR 1 month after transplantation was lower in the intervention group versus the control group. Compared with controls, patients in the intervention group received significantly lower daily doses of everolimus and nonsignificantly lower doses of cyclosporin A, resulting in significantly lower trough levels of everolimus (3.5 versus 4.5 µg/L, P<0.001) and cyclosporin A (47.4 versus 64.1 µg/L, P<0.001). Only 20% of patients in the intervention group versus 47% in the control group received glucocorticoids 2 years after transplantation (P=0.04). The groups had similar numbers of donor-specific antibodies and serious adverse events. CONCLUSIONS:Steering immunosuppressive therapy by virus-specific T cell levels in addition to pharmacokinetic monitoring seems safe, results in a similar eGFR, and personalizes immunosuppressive therapy by lowering exposure to immunosuppressive drugs, likely resulting in lower drug costs. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER:IVIST trial, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2009-012436-32 and ISRCTN89806912. |
|||||||||||||||
Clin Transplant. 2019 Oct;33(10):e13698 doi: 10.1111/ctr.13698.
CET Conclusion
BACKGROUND AND AIMS:
This multicenter trial compared immediate-release tacrolimus (IR-T) vs prolonged-release tacrolimus (PR-T) in de novo kidney, liver, and heart transplant recipients aged <16 years. Each formulation had similar pharmacokinetic (PK) profiles. Follow-up efficacy and safety results are reported herein. MATERIALS AND METHODS:Patients, randomized 1:1, received once-daily, PR-T or twice-daily, IR-T within 4 days of surgery. After a 4-week PK assessment, patients continued randomized treatment for 48 additional weeks. At Year 1, efficacy assessments included the number of clinical acute rejections, biopsy-confirmed acute rejection (BCAR) episodes (including severity), patient and graft survival, and efficacy failure (composite of death, graft loss, BCAR, or unknown outcome). Adverse events were assessed throughout. RESULTS:The study included 44 children. At Year 1, mean ± standard deviation tacrolimus trough levels were 6.6 ± 2.2 and 5.4 ± 1.6 ng/mL, and there were 2 and 7 acute rejection episodes in the PR-T and IR-T groups, respectively. No cases of graft loss or death were reported during the study. The overall efficacy failure rate was 18.2% (PR-T n = 1; IR-T n = 7). CONCLUSIONS:In pediatric de novo solid organ recipients, the low incidence of BCAR and low efficacy failure rate suggest that PR-T-based immunosuppression is effective and well tolerated to 1-year post-transplantation. |
|||||||||||||||
Pediatr Transplant. 2018 Nov;22(7):e13285 doi: 10.1111/petr.13285.
CET Conclusion
BACKGROUND:
Tacrolimus pharmacokinetics are influenced by age and CYP3A5 genotype with CYP3A5 expressors (CYP3A5*1/*1 or *1/*3) being fast metabolizers. However, the benefit of genotype-guided dosing in pediatric solid organ transplantation has been understudied. OBJECTIVE:To determine whether age and CYP3A5 genotype-guided starting dose of tacrolimus result in earlier attainment of therapeutic drug concentrations. SETTING:Single hospital-based transplant center. METHODS:This was a randomized, semi-blinded, 30-day pilot trial. Between 2012 and 2016, pediatric patients listed for solid organ transplant were consented and enrolled into the study. Participants were categorized as expressors, CYP3A5*1/*1 or CYP3A5*1/*3, and nonexpressors, CYP3A5*3/*3. Patients were stratified by age (≤ or > 6 years) and randomized (2:1) after transplant to receive genotype-guided (n = 35) or standard (n = 18) starting dose of tacrolimus for 36-48 hours and were followed for 30 days. RESULTS:Median age at transplant in the randomized cohort was 2.1 (0.75-8.0) years; 24 (45%) were male. Participants in the genotype-guided arm achieved therapeutic concentrations earlier at a median (IQR) of 3.4 (2.5-6.6) days compared to those in the standard dosing arm of 4.7 (3.5-8.6) days (P = 0.049), and had fewer out-of-range concentrations [OR (95% CI) = 0.60 (0.44, 0.83), P = 0.002] compared to standard dosing, with no difference in frequency of adverse events between the two groups. CONCLUSIONS:CYP3A5 genotype-guided dosing stratified by age resulted in earlier attainment of therapeutic tacrolimus concentrations and fewer out-of-range concentrations. |
|||||||||||||||
Pediatr Nephrol. 2008 Mar;23(3):499-501 doi: 10.1007/s00467-007-0655-3.
The aim of our study was to investigate the effect of tangerine juice on the pharmacokinetics of cyclosporine A (CsA), in children who had received a renal transplant. This placebo-controlled study was done on ten kidney transplant recipients with stable cyclosporine trough levels who received either tangerine (Unshio Satsuma) juice or water. Patients were given their morning doses of CsA and then 250 ml water or the juice, and 12 h, investigations of the pharmacokinetics (PK) were performed. The main outcome measures were peak concentration and time to peak and area under the concentration-time curve. Administration of CsA with tangerine juice compared with water did not increase significantly the area under the whole-blood concentration versus time curve from 0-12 h (AUC(0-12)) of CsA, (tangerine juice 2,797 +/- 1,361 (P = 0.5); water 3,053 +/- 1,532). Co-administration of tangerine juice with CsA compared with water had no significant effects on the AUC(0-12), peak concentration (C(max)) or time to C(max) (t(max)) of the CsA in pediatric renal transplantation. |
|||||||||||||||
Transplantation. 2008;86(9):1234-40.
BACKGROUND: The aim of this substudy within a prospective, multicenter, placebo-controlled trial was to assess the pharmacokinetics and immunodynamics of basiliximab in pediatric renal transplant recipients on comedication with mycophenolate mofetil (MMF). METHODS: Eighty-two patients aged 3 to 18 years, receiving cyclosporine microemulsion, MMF, corticosteroids, and basiliximab or placebo were investigated. Basiliximab serum concentrations were determined by ELISA, CD25+, and CD122+ T lymphocytes by flow cytometry. RESULTS: Basiliximab clearance adjusted to body surface area was significantly (P<0.05) greater in children versus adults, but the relatively higher basiliximab dose given to children yielded similar exposure compared with adolescents. A cross-study comparison revealed that MMF reduced basiliximab clearance and prolonged CD25 saturation duration from approximately 5 weeks in the absence of MMF to 10 weeks in the presence of MMF. Basiliximab led to a marked reduction of CD25+ T-cell fraction during the first 8 to 10 weeks posttransplant, but did not specifically affect CD122+ T cells. The majority of biopsy-proven acute rejection episodes (BPAR) were observed after interleukin (IL) 2-R desaturation, whereas about a quarter of BPARs occurred despite adequate IL2-R blockade. CONCLUSIONS: The currently recommended basiliximab dose for pediatric patients, when used with cyclosporine microemulsion and corticosteroids, yielded adequate drug exposure in children and adolescents also under MMF comedication. The observation that about a quarter of BPARs occurred despite adequate IL2-R blockade suggests that another T-cell activation pathway independent of the IL-2/IL-2R pathway is operative, for example, the IL-15 signaling pathway.
|
|||||||||||||||
Pediatr Transplant. 2006 Dec;10(8):914-9 doi: 10.1111/j.1399-3046.2006.00541.x.
We have previously reported sirolimus (SRL) pharmacokinetics (PK) in pediatric renal transplant recipients on a calcineurin inhibitor (CNI)-free protocol. We now report pediatric SRL PK in pediatric renal transplant patients receiving SRL + CNI. SRL was dosed to achieve target trough levels between 10 and 20 ng/mL. We performed 49 SRL PK profiles in pediatric renal transplant recipients receiving SRL in combination with either cyclosporine (CsA; 25 profiles), or tacrolimus (TCL; 24 profiles). Ten of the SRL + TCL profiles were obtained from children receiving SRL on a b.i.d. dosing regimen. All other SRL profiles were q.d. regimens. We calculated, the maximum concentration (C(max)), AUC, apparent clearance (aCL; dose/AUC) for dose in mg/m(2), and mean residence time (MRT). SRL levels were measured at 6 and 7 time points for b.i.d. and q.d. dosing, respectively. Regression analysis of SRL trough values vs. AUC showed good correlation in the SRL q.d. + CsA, SRL q.d. + TCL, and SRL b.i.d. + TCL groups (r(2) = 0.95, 0.68, and 0.44, respectively). SRL aCL corrected for body surface area was higher in children aged 0-5 yr receiving SRL with either CsA or TCL. SRL dosing schedule should be tailored to each patient. Higher SRL aCL may be present in younger children when administered with CNI. |
|||||||||||||||
J Heart Lung Transplant. 2005 Feb;24(2):190-4 doi: 10.1016/j.healun.2004.11.006.
BACKGROUND:
While Tacrolimus (Tac) and Cyclosporine (Cya) immunosuppression are used after cardiac transplantation (tx), few studies have evaluated their use in pediatric patients. METHODS:We randomized 26 heart transplant recipients (pts) in a prospective, open-label trial to Tac (n = 14) or Cya (n = 12) to compare their efficacy and side-effects. Mean age at tx was 4.2 years for Tac and 5.8 years for Cya. Mean follow-up was 26 months (range: 11-39 months) for Tac and 24 months for Cya (range: 33-13 months). RESULTS:Our data suggest that both regimens are efficacious in the pediatric population. Conversion from Cya to Tac was useful for dealing with persistent rejection, although this sample did not suggest lower incidence of acute cellular rejection in the Tac group. CONCLUSIONS:Further studies are required to establish pharmacokinetic parameters to enhance therapeutic monitoring of these patients to minimize side effects and enhance outcomes. |
|||||||||||||||
Pediatr Transplant. 2004 Apr;8(2):151-60 doi: 10.1046/j.1399-3046.2003.00137.x.
Sirolimus (Rapamune, rapamycin) has been shown to be an effective and safe immunosuppressive drug in adult kidney transplant patients when administered concomitantly with cyclosporine (CsA) and steroids. This study reports on a phase 1 assessment of the drug's tolerance, safety, and pharmacokinetic parameters in pediatric patients. The safety and pharmacokinetic profiles of ascending single doses of sirolimus oral solution were investigated in 32 clinically stable pediatric patients on chronic hemodialysis (n = 26) or peritoneal dialysis (n = 6). Patients were divided into two age groups (5-11 and 12-18 yr), and each patient received either a single dose of sirolimus (1, 3, 9, or 15 mg/m(2)) or placebo. Whole blood and plasma samples were collected from each patient for the determination of sirolimus pharmacokinetic parameters. Safety assessments were based on reports of adverse events and results of scheduled physical examinations, vital sign measurements and clinical laboratory tests. The younger patients (5-11 yr) showed statistically significant increases in whole blood sirolimus t(max) (p < or = 0.05) and weight-normalized CL/F (p<0.05) when compared with older patients (12-18 yr). There were no differences in terminal t(1/2), V(ss)/F, dose-normalized peak concentration (C(max)) and AUC, or the B/P. The whole blood sirolimus mean t(max) and weight-normalized CL/F in younger patients were increased by approximately 41.5% and 30%, respectively. Whole blood sirolimus concentrations exhibited less than proportional increases with ascending doses, which may have been caused by the large inter-subject variability in CL/F, small number of subjects, and a potentially inherent decrease in sirolimus bioavailability in younger pediatric patients. Adverse events occurred in all dose and age groups, with headache and stomach pain being the most frequently observed events. No deaths or serious adverse events were reported, and no patient withdrew from the study because of an adverse event. Based on an inter-study analysis, weight-normalized CL/F in the current population of younger pediatric dialysis patients (5-11 yr, 544 +/- 463 mL/h/kg, n = 7) was increased by 90% (p < or = 0.05) compared with healthy adults (19-36 yr, 287 +/- 111 mL/h/kg, n = 25). These results suggest that younger pediatric patients might require an increased maintenance dose of sirolimus to achieve whole blood exposures similar to those in healthy adults. Sirolimus is well tolerated as a single dose of 1, 3, 9, or 15 mg/m(2). |
|||||||||||||||
J Clin Pharmacol. 2003 Feb;43(2):141-7 doi: 10.1177/0091270002239822.
The immunosuppressant everolimus used in organ transplantation is formulated as a conventional tablet for adults and a dispersible tablet that can be administered in water for pediatric use. As part of the pediatric clinical development program, the relative bioavailability and food effect for the dispersible tablet were evaluated in healthy adult subjects as a prelude to characterizing the steady-state pharmacokinetics in pediatric kidney allograft recipients. In a randomized, open-label, three-way crossover study, 24 healthy adults received single 1.5-mg oral doses of everolimus as (1) six 0.25-mg dispersible tablets in water, (2) two 0.75-mg conventional tablets, and (3) six 0.25-mg dispersible tablets in water after a high-fat breakfast. Cmax and AUC were evaluated by standard bioequivalence testing to determine relative bioavailability and to quantify the effect of food. In a multicenter open-label efficacy/safety trial, pediatric renal allograft recipients received 0.8 mg/m2 (maximum 1.5 mg) bid everolimus as dispersible tablets in water. Serial trough concentrations over the first week and a steady-state pharmacokinetic profile on day 7 posttransplant were collected in 19 patients ranging from ages 2 to 16 years old. The bioavailability of everolimus from the dispersible tablet was 10% lower relative to the conventional tablet, with a ratio (90% confidence interval) of 0.90 (0.76-1.07). After a high-fat meal, tmax was delayed by a median 2.5 hours, and Cmax was reduced by 50%. Overall absorption, however, was not affected by food inasmuch as the fed/fasting AUC ratio was 0.99 (0.83-1.17). In pediatric patients, steady state was reached between days 3 and 5. The corresponding steady-state parameters were as follows: Cmin, 4.4 +/- 1.7 ng/ml; Cmax, 13.6 +/- 4.2 ng/ml; and AUC, 87 +/- 27 ng.h/ml. Steady-state concentration-time profiles in pediatric transplant patients receiving the dispersible tablet were comparable to those of adult patients receiving the conventional tablet when both were dosed to yield similar trough concentrations. If a pediatric patient is converted from the everolimus dispersible tablet to the conventional tablet, this should be based on a 1:1 milligram switch with subsequent therapeutic drug monitoring to further individualize the dose as needed. The dispersible tablet formulation should be taken consistently either with or without food to minimize fluctuations in exposure over time. |
|||||||||||||||
J Ren Nutr. 2003 Jan;13(1):26-30 doi: 10.1053/jren.2003.50006.
OBJECTIVE:
Determine whether olestra alters the absorption of cyclosporine microemulsion in pediatric renal transplant recipients. DESIGN:Prospective, open-label, crossover pharmacokinetic study. SETTING:General clinical research center in a university medical setting providing tertiary care. PARTICIPANTS:Seven pediatric-adolescent renal transplant recipients, ages 9 to 18, 5 to 24 months post-transplant with mean serum creatinine of 0.9 mg/dL (range, 0.7-1.6 mg/dL). METHODOLOGY:Patients participated in 2 study periods: 1. Patients were given their usual dose of Neoral (Novartis Pharmaceuticals Corporation, East Hanover, NJ) without olestra, 2. patients were given their usual dose of Neoral combined with 0.35 g/kg (maximum of 16 g of olestra or approximately 2 ounces of Lays WOW [Frito Lay, Plano, TX] potato chips). The 2 study periods were separated by a minimum 7-day washout period. CsA blood concentrations were obtained at 1, 2, 3, 4, 6, 8, and 12 hours after drug administration. RESULTS:Each patient in the study had a consistent decrease in area under the curve (AUC) when given olestra along with their usual dose of Neoral, compared with giving Neoral alone (5,018 ng*hr/mL versus 4,086 ng*hr/mL; P <.001). There also was a decrease in maximum concentration (Cmax) when Neoral was given with olestra compared with giving Neoral alone (1,202 ng/mL versus 876 ng/mL; P =.015). There was no statistical difference in the mean elimination rate or the trough values for both regimens (half-life 4.767 hours versus 4.771 hours and trough levels of 143 ng/mL versus 124 ng/mL). CONCLUSION:Olestra decreases total CsA exposure in pediatric renal transplant recipients. The noted decrease in AUC was not adequately predicted by CsA trough values which could lead to rejection episodes in the clinical setting. |