Feasibility of steroid-free tacrolimus-basiliximab immunosuppression in pediatric liver transplantation and predictors for steroid requirement.

Avoidance of steroids in pediatric liver transplantation may reduce toxicity and morbidity. The aim of this study was to analyze the feasibility of a steroid-free tacrolimus-basiliximab immunosuppression scheme, the risk factors associated with steroid requirement, and safety parameters. Patients who underwent liver transplantation for biliary atresia between 2011 and 2019 were included and followed for 6 months after transplantation. Immunosuppression consisted of tacrolimus-based treatment with basiliximab induction. Steroid-free survival was estimated, and risk factors for steroid requirement were evaluated using multivariate Cox regression analysis. A total of 76 patients were included, of whom 42 (55.3%) required steroids (>14 d) due to biopsy-proven acute rejection (47.6%, n = 20), instability in liver function tests (35.7%, n = 15), tacrolimus-related adverse drug reactions (14.3%, n = 6), or other reasons (bronchospasm episode, n = 1). Steroid-free survival was 45.9% (95% CI, 35.9-58.8). Independent factors associated with steroid requirement included tortuosity in tacrolimus trough levels (≥1.76 vs. <1.76: HR 5.8, 95% CI, 2.6-12.7; p < 0.001) and mean tacrolimus trough levels (≥ 6.4 ng/mL vs. < 6.4 ng/mL: HR 0.4, 95% CI, 0.2-0.7; p = 0.002). The rate of bacterial and viral infections was comparable between patients with and without steroids, although in the former group, cytomegalovirus infection developed earlier ( p = 0.03). Patients receiving steroids had higher total cholesterol, LDL, and HDL levels ( p < 0.05) during follow-up, but no changes in the height Z-score were observed 1 year after transplantation. Basiliximab induction in combination with tacrolimus-based treatment avoided steroid requirements in 45% of the patients. Tacrolimus variability and trough levels below 6.4 ng/mL independently increased the risk of steroid requirement. Further efforts should be focused on personalizing immunosuppressive treatment.

Population pharmacokinetics of sublingually administered tacrolimus in infants and young children with liver transplantation.

AIMS: Pharmacokinetics of tacrolimus after sublingual administration is not characterized in paediatric liver transplant patients. Therefore, we aimed to develop a population pharmacokinetic model of sublingually administered tacrolimus in patients who cannot swallow the capsules due to their age, sedation status and/or mechanical ventilation during the first weeks post-transplantation. METHODS: Demographic, clinical and pharmacological variables, including tacrolimus whole blood concentrations obtained from therapeutic drug monitoring and data from dense-sampling pharmacokinetic profiles, were recorded in 26 paediatric patients with biliary atresia who underwent liver transplantation between 2016 and 2021. Population pharmacokinetic analysis was performed with NONMEM v7.4. RESULTS: Disposition of tacrolimus was best characterized by a 2-compartment model with clearance achieving half of the maximum elimination capacity (CLMAX  = 4.1 L/h) at 4.6 days post-transplantation (T50 ). Compared to sedated patients, nonsedated status showed an increased first-order absorption rate constant (1.1 vs. 0.1 h-1 ) and a 24% reduction in bioavailability (FNS ) at 14 days post-transplant. The model was able to explain the oral absorption pattern in nonsedated patients as the result of gut bioavailability (0.9) and hepatic extraction ratio, with the latter being responsible for first-pass effects. Estimates of interindividual variability remained moderate (25.9% for the gut bioavailability) to high (79.8% for the apparent volume of distribution of the central compartment, and 101% for T50 ). CONCLUSION: A population pharmacokinetic model of sublingually administered tacrolimus in paediatric patients was developed to characterize different absorption mechanisms. Once the model is externally validated, the effect of post-transplant time on clearance and the sedation status may be considered in routine dosing management.

[Performance evaluation of a precision dosing service for vancomycin in a tertiary level pediatric hospital]. / Una evaluación de desempeño del servicio de dosificación de precisión para vancomicina en un hospital pediátrico de nivel terciario.

Background: Plasma level-based therapeutic drug monitoring of vancomycin is recommended in the treatment of complex pediatric infections in order to increase the probability of achieving safe and effective pharmacotherapy. Objective: To retrospectively evaluate the activities and performance of pharmacotherapeutic optimization based on vancomycin levels at a tertiary pediatric hospital between 2007 and 2020. Métodos: Vancomycin levels of pediatric patients were analyzed, assessing care quality indicators and analytical verifications, as well as aspects related to teaching and research. The predictive performance of vancomycin levels was evaluated after adjustment of the therapeutic regimen using a population pharmacokinetic optimization program (BestDose v1.126) considering the coefficient of determination (R2), the mean absolute percentage error (MAPE), and the root mean square error (RMSE). Results: 13269 vancomycin level determinations were analyzed; 70% were trough levels and 81% belonged to patients in the intensive care units. Forty percent of the trough levels were within the therapeutic range when adjusted without software. Three hundred seventy-four pharmacotherapeutic interventions, of which 97% were accepted by the treating physician; 75% of the post-adjustment trough levels were within the therapeutic range, compared to 40% when the approach was empirical, a difference that was statistically significant (p=0.03). The values associated with predictive performance (n subgroup of patients = 91) were: R2=0.61, MAPE=28.16%, and RMSE=3.3, which all showed to be adequate. Conclusion: The performance of therapeutic vancomycin monitoring and related pharmacokinetic clinical activities showed to be good.

Introducción: La dosificación de precisión a través del monitoreo de vancomicina basado en sus concentraciones plasmáticas (vancocinemia) es una práctica recomendada en el tratamiento de infecciones pediátricas de alta complejidad para aumentar la probabilidad de lograr una farmacoterapia segura y eficaz. Objetivo: Evaluar retrospectivamente las actividades y el desempeño relacionado a la optimización farmacoterapéutica basada en las vancocinemias (período 2007-2020) de un hospital pediátrico terciario. Métodos: Se analizaron las vancocinemias de pacientes pediátricos, estimándose indicadores de calidad asistencial y verificaciones analíticas, así como también aspectos relacionados a docencia e investigación. Se evaluó el desempeño predictivo de las concentraciones de vancomicina cuando se ajustaron los regímenes terapéuticos con un programa de optimización farmacocinética (BestDose v1.126) considerando el coeficiente de determinación (R2), el error porcentual absoluto medio (MAPE) y la raíz del error cuadrático medio (RMSE). Resultados: Se analizaron 13269 vancocinemias. El 70% fueron valles y el 81% pertenecieron a pacientes de Unidades de Cuidados Intensivos. El 40% de los valles se encontró dentro del margen terapéutico al ajustarse sin programa informático. Se realizaron 347 intervenciones farmacoterapéuticas, el 97% de las cuales fueron aceptadas por el médico tratante; el 75% de los valles posteriores al ajuste entraron en el margen terapéutico, valor significativamente mayor respecto al 40% de cuando el abordaje fue empírico (p=0.03). Los valores asociados al desempeño predictivo, (n subgrupo de pacientes = 91) fueron: R2=0.61, MAPE=28.16% y RMSE=3.3, mostrándose todos adecuados. Conclusión: Las actividades de monitoreo y farmacocinética clínica de vancomicina mostraron un buen rendimiento clínico. Resultados: Se analizaron 13269 vancocinemias. El 70% fueron valles y el 81% pertenecieron a pacientes de Unidades de Cuidados Intensivos. El 40% de los valles se encontró dentro del margen terapéutico al ajustarse sin programa informático. Se realizaron 347 intervenciones farmacoterapéuticas, el 97% de las cuales fueron aceptadas por el médico tratante; el 75% de los valles posteriores al ajuste entraron en el margen terapéutico, valor significativamente mayor respecto al 40% de cuando el abordaje fue empírico (p=0.03). Los valores asociados al desempeño predictivo, (n subgrupo de pacientes = 91) fueron: R2=0.61, MAPE=28.16% y RMSE=3.3, mostrándose todos adecuados. Conclusión: Las actividades de monitoreo y farmacocinética clínica de vancomicina mostraron un buen rendimiento clínico.

Population pharmacokinetics of amikacin in patients with pediatric cystic fibrosis.

INTRODUCTION: Amikacin is commonly used in patients with pediatric cystic fibrosis (CF) for the treatment of pulmonary exacerbations. Amikacin efficacy is related to maximum plasma concentration/minimum inhibitory concentration (Cmax/MIC) ratio >8. Pharmacokinetic data in patients with pediatric CF are scarce. The aim of this study was to develop a population pharmacokinetic (PopPK) model describing amikacin disposition in patients with pediatric CF. METHODS: CF patients under 18 years of age with pulmonary exacerbation who received amikacin were enrolled. Patients received different amikacin regimens (30 mg-1 kg-1 day-1 every 8, 12, or 24 hours) depending on the patient's status and hospital protocols. Amikacin serum levels were obtained for therapeutic drug monitoring. PopPK model was developed using MONOLIX Suite-2018R1 (Lixoft). RESULTS: A total of 39 patients (114 amikacin concentrations) were included in this study. Population estimates for the elimination rate constant (k) and the volume of distribution (V) were 0.541 hours-1 and 0.451 L/kg, respectively. Between-subject and between-occasion variability were 53% and 16.5% for k and 31% and 22% for V, respectively. Bodyweight was a significant covariate associated with V. Based on simulations, almost 70% of the patients receiving 30 mg-1 kg-1 day-1 every 24 hours would achieve a Cmax/MIC ratio >8 which is an appropriate therapeutic goal while no patient in the other two groups (Q8 and Q12) would achieve that objective. CONCLUSIONS: The regimen of 30 mg-1 kg-1 day-1 every 24 hours more adequately fulfilled the therapeutic target for amikacin. Although all our patients had good clinical results and a good adverse-events profile, further studies are necessary to redefine the optimal treatment strategy.

Identification of Factors Affecting Tacrolimus Trough Levels in Latin American Pediatric Liver Transplant Patients.

Tacrolimus is the cornerstone in pediatric liver transplant immunosuppression. Despite close monitoring, fluctuations in tacrolimus blood levels affect safety and efficacy of immunosuppressive treatments. Identifying the factors related to the variability in tacrolimus exposure may be helpful in tailoring the dose. The aim of the present study was to characterize the clinical, pharmacological, and genetic variables associated with systemic tacrolimus exposure in pediatric liver transplant patients. De novo transplant patients with a survival of more than 1 month were considered for inclusion and were genotyped for cytochrome P450 3A5 (CYP3A5). Peritransplant clinical factors and laboratory covariates were recorded retrospectively between 1 month and 2 years after transplant, including alanine aminotransferase (ALT), aspartate aminotransferase, hematocrit, and tacrolimus predose steady-state blood concentrations collected 12 hours after tacrolimus dosing. A linear mixed effect (LME) model was used to assess the association of these factors and the log-transformed tacrolimus dose-normalized trough concentration (logC0/D) levels. Bootstrapping was used to internally validate the final model. External validation was performed in an independent group of patients who matched the original population. The developed LME model described that logC0/D increases with increases in time after transplant (ß = 0.019, 95% confidence interval [CI], 0.010-0.028) and ALT values (ß = 0.00030, 95% CI, 0.00002-0.00056), whereas logC0/D is significantly lower in graft CYP3A5 expressers compared with nonexpressers (ß = -0.349, 95% CI, -0.631 to -0.062). In conclusion, donor CYP3A5 genotype, time after transplant, and ALT values are associated with tacrolimus disposition between 1 month and 2 years after transplant. A better understanding of tacrolimus exposure is essential to minimize the occurrence of an out-of-range therapeutic window that may lead to adverse drug reactions or acute rejection.

Survival Time to Biopsy-Proven Acute Rejection and Tacrolimus Adverse Drug Reactions in Pediatric Liver Transplantation.

BACKGROUND: Despite advances in surgical procedures and the optimization of immunosuppressive therapies in pediatric liver transplantation, acute rejection (AR) and serious adverse drug reaction (ADR) to tacrolimus still contribute to morbidity and mortality. Identifying risk factors of safety and efficacy parameters may help in optimizing individual immunosuppressive therapies. This study aimed to identify peritransplant predictors of AR and factors related to the risk of ADR to tacrolimus in a large Latin American cohort of pediatric liver transplant patients. METHODS: We performed a retrospective cohort study in a pediatric liver transplant population (n = 72). Peritransplant variables were collected retrospectively including demographic, clinical, laboratory parameters, genomic (CYP3A5 donor and recipients polymorphism), and tacrolimus trough concentrations (C0) over a 2-year follow-up period. Variability in tacrolimus C0 was calculated using percent coefficient of variation and tortuosity. ADR- and AR-free survival rates were calculated using the Kaplan-Meier method, and risk factors were identified by multivariate Cox regression models. RESULTS: Cox-proportional hazard models identified that high tortuosity in tacrolimus C0 was associated with an 80% increased risk of AR [hazard ratio (HR), 1.80; 95% confidence interval (CI), 1.01-3.22; P < 0.05], whereas steroid in maintenance doses decreased this risk (HR, 0.56; 95% CI, 0.31-0.99; P < 0.05). Forty-six patients experienced at least one ADR including hypomagnesemia, nephrotoxicity, hypertension, malignancies, and tremor as a first event. Multivariate analysis showed that C0 values 10 days before the event (HR, 1.25; 95% CI, 1.21-1.39; P < 0.0001) and CYP3A5 expresser recipients (HR, 2.05; 95% CI, 1.03-4.06; P < 0.05) were independent predictors of ADR. CONCLUSIONS: Tacrolimus C0 values, its variability, and CYP3A5 polymorphisms were identified as risk factors of AR and tacrolimus ADR. This knowledge may help to control and reduce their incidence in pediatric liver transplant patients. Prospective studies are important to validate these results.

Therapeutic monitoring of pediatric transplant patients with conversion to generic tacrolimus.

OBJECTIVE: Therapeutic monitoring during interchange of tacrolimus commercial formulations is essential to ensure similar exposure in transplant patients. However, there are limited data in the pediatric transplant population. This study aims to evaluate exposure, safety and efficacy in maintenance pediatric transplant patients under generic tacrolimus substitution. METHOD: Pediatric patients who underwent interchange of tacrolimus formulations were detected by the Service of Pharmacy and included in this study. Tacrolimus trough levels (C0), laboratory parameters and clinical characteristics were recorded before and after the switch. Statistical analysis was performed using Wilcoxon matched pair t-test. RESULTS: In total, 10 patients with kidney, liver, heart and hematopoietic stem cell transplantation received the innovator and switched to the generic product. The median (range) of the C0 normalized by the dose before and after switch was 74.8 [(ng/ml)/(mg/kg)] (13.8-518.4) and 65.1 [(ng/ml)/(mg/kg)] (13.5-723.5), respectively (p>0.05). Tacrolimus dose was 0.070(mg/kg) (0.024-0.461) and 0.069(mg/kg) (0.017- 0.571) for the innovator and generic formulation, respectively, with no difference when comparing both values (p>0.05). Laboratory parameters did not change after conversion (p>0.05). Adverse events, acute rejection, death and graft loss were not observed. CONCLUSION: In our study population, no significant differences in terms of laboratory parameters, drug exposure and dose were observed. We emphasize the need of close monitoring to ensure a safe interchange, especially in vulnerable populations such as the pediatric.

Objetivo: La monitorización terapéutica durante el intercambio de marcas comerciales de inmunosupresores es esencial para mantener una similar exposición al fármaco en pacientes trasplantados. Sin embargo, la información disponible en trasplante pediátrico es limitada. El objetivo del trabajo fue evaluar la exposición, seguridad y eficacia en pacientes pediátricos trasplantados en etapa de mantenimiento, sujetos a intercambio entre el producto innovador y el genérico de tacrolimus. Método: El Área de Farmacia del hospital detectó aquellos pacientes sujetos a intercambio de formulaciones según la disponibilidad de medicamentos. Se obtuvieron las concentraciones de tacrolimus en el valle (C0), parámetros de laboratorio y características clínicas antes y después del intercambio. El análisis estadístico se realizó mediante el test de muestras pareadas de Wilcoxon. Resultados: Se incluyeron 10 pacientes con trasplante renal, hepático, cardíaco y de células hematopoyéticas. La mediana (rango) del C0 normalizado por la dosis pre y post intercambio fue 74,8[(ng/ml)/(mg/kg)](13,8-518,4) y 65,1[(ng/ml)/(mg/kg)] (13,5-723,5), respectivamente (p>0,05). La dosis de tacrolimus fue 0,070(mg/kg) (0,024-0,461) y 0,069(mg/kg) (0,017-0,571) para el innovador y el genérico, respectivamente (p>0,05). Los parámetros de laboratorio de funcionalidad renal y hepática no cambiaron con la conversión de marcas (p>0,05). No se observaron eventos adversos, rechazo agudo, muerte o pérdida del injerto durante el periodo analizado. Conclusiones: En la población estudiada, no se observaron diferencias significativas en los parámetros de laboratorio, exposición al tacrolimus o dosis en el intercambio de marcas comerciales. Destacamos el rol de la monitorización terapéutica a la hora de garantizar una sustitución segura, especialmente en poblaciones vulnerables.

Therapeutic monitoring of pediatric renal transplant patients with conversion to generic cyclosporin.

BACKGROUND: Cyclosporin is a calcineurin inhibitor widely used in renal transplant patients to prevent organ rejection. Several position papers have been published but no reports on the practical experience in pediatric patients undergoing conversion between cyclosporin innovator and generic products are available. OBJECTIVE: To evaluate the pharmacokinetics and safety as part of therapeutic monitoring of cyclosporin in renal transplant pediatric patients who switch from the innovator to the generic formulation in Argentina. SETTING: Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina. METHODS: Stable pediatric renal transplant patients (6 months post-transplant) switched from the innovator to the generic formulation of cyclosporin microemulsion capsule. Cyclosporin pharmacokinetic parameters were obtained while taking the innovator and after starting with the generic formulation. Blood samples were drawn before and 1, 2, and 3 h after drug administration and subsequently quantified. Pharmacokinetic parameters were obtained by means of a Bayesian approach. MAIN OUTCOMES MEASURE: Cyclosporin pharmacokinetic parameters (area under the curve, AUC; Blood concentration after 2 h, C2), adverse events and graft rejection. RESULTS: A total of 12 patients were included. Median (range) age and time post-transplant were 10.7 years (6.5-17.7) and 8.3 years (3.4-14.0), respectively. Two patients or their parents did not consent to the switch. Median (range) dose normalized cyclosporin AUC and C2 were 1.15 (mg*h/L)/mg/kg (0.72-3.0) and 265.5 (ng/ml)/mg/kg (120.8-725.7), respectively, on the innovator therapy and 1.05 (mg*h/L)/mg/kg (0.54-2.22) and 317.1 (ng/ml)/mg/kg (116.7-564.7) for the generic drug after the switch. The median (range) percentage of change in the AUC and C2 when switching between formulations were 16.7 % (0.7-56.7) and 13.1 % (3.7-68.6), respectively. No significant changes in serum creatinine levels were registered when comparing before and after substitution of products. Adverse events (number of events) recorded 5 months before and after the switch included hirsutism (2), hypertension (2), and gingival hyperplasia (1). CONCLUSION: Conversion of cyclosporin from innovator brand to generic in pediatric renal transplant patients needs to be closely monitored.