Cost-Effectiveness of Therapeutic Drug Monitoring of Anti-TNF Therapy in Inflammatory Bowel Disease: A Systematic Review.

Infliximab and adalimumab are monoclonal antibodies against tumor necrosis factor (anti-TNF) used to manage inflammatory bowel disease (IBD). Therapeutic Drug Monitoring (TDM) has been proven to prevent immunogenicity, to achieve better long-term clinical results and to save costs in IBD treatment. The aim of this study was to conduct a systematic review on cost-effectiveness analyses of studies that apply TDM of anti-TNF in IBD and to provide a critical analysis of the best scientific knowledge available in the literature. The quality of the included studies was assessed using Consolidated Health Economic Evaluation Reporting Standards (CHEERS). Cost-effectiveness of the TDM strategies was presented as total costs, cost savings, quality-adjusted life-years (QALY) and incremental cost-effectiveness ratio (ICER). Thirteen studies that examined the health economics of TDM of anti-TNF in IBD from 2013 to 2021 were included. Eight of them (61.5%) achieved a score between 17 and 23 on the CHEERS checklist. The comparison between the TDM strategy and an empirical strategy was cost saving. The ICER between reactive TDM and an empirical strategy was dominated (favorable) by reactive TDM, whereas the ICER value for proactive TDM compared to an empirical strategy ranged from EUR 56,845 to 3,901,554. This systematic review demonstrated that a TDM strategy is cost-effective or cost-saving in IBD.

Evaluation of the Predictive Performance of Population Pharmacokinetic Models of Adalimumab in Patients with Inflammatory Bowel Disease.

Adalimumab is a monoclonal antibody used for inflammatory bowel disease. Due to its considerably variable pharmacokinetics, the loss of response and the development of anti-antibodies, it is highly recommended to use a model-informed precision dosing approach. The aim of this study is to evaluate the predictive performance of different population-pharmacokinetic models of adalimumab for inflammatory bowel disease to determine the pharmacokinetic model(s) that best suit our population to use in the clinical routine. A retrospective observational study with 134 patients was conducted at the General University Hospital of Alicante between 2014 and 2019. Model adequacy of each model was evaluated by the distribution of the individual pharmacokinetic parameters and the NPDE plots whereas predictive performance was assessed by calculating bias and precision. Moreover, stochastic simulations were performed to optimize the maintenance doses in the clinical protocols, to reach the target of 8 mg/L in at least 75% of the population. Two population-pharmacokinetic models were selected out of the six found in the literature which performed better in terms of adequacy and predictive performance. The stochastic simulations suggested the benefits of increasing the maintenance dose in protocol to reach the 8 mg/L target.

Population pharmacokinetics models of sirolimus in renal transplant patients: A systematic review.

OBJECTIVE: Sirolimus is used in the immunosuppressive therapeutic treatment  of kidney transplant patients. The high pharmacokinetic variability of sirolimus  makes pharmacokinetic monitoring and dosage individualization of  mmunosuppressive therapy a key process to achieve better efficacy results.  The availability of a population pharmacokinetic model can be used to provide  better pharmacokinetic adjustment of plasma concentrations of sirolimus and  thus achieve greater clinical benefit. METHOD: We conducted a systematic review of the literature available in the  Medline, Embase, and Scopus databases to identify and subsequently analyze  population pharmacokinetic models of orally administered sirolimus in adult  patients after kidney transplant. The descriptors used MeSH were kidney  transplantation, pharmacokinetics, and sirolimus. The following variables from  the selected studies were assessed: study population, immunosuppressive  treatment, blood sampling times, covariates analyzed, type of pharmacokinetic  model, computer software used, estimated pharmacokinetic  parameters, interindividual variability of pharmacokinetic parameters, residual  variability and mathematical equations of the pharmacokinetic model. RESULTS: A total of 548 results were obtained, excluding 175 records that were  identified in more than one database. Finally, seven articles that  et  the inclusion criteria were selected. Most of the pharmacokinetic models found fit a two-compartment model. The interindividual variability of sirolimus  was explained by covariates such as age, weight, liver function, cyclosporine exposure and dose, sirolimus doses, CYP3A5 genetic  olymorphisms, serum creatinine, and concomitant treatment. CONCLUSIONS: The two-compartment model was the pharmacokinetic model of  choice in most of the selected studies. The interindividual variability of the  pharmacokinetic parameters of sirolimus is explained by demographic, clinical,  genetic, and biochemical variables. The availability of pharmacokinetic models  of sirolimus can assist in optimizing therapy in patients after kidney transplant.

OBJETIVO: Sirólimus es un fármaco utilizado en los esquemas terapéuticos inmunosupresores en pacientes con trasplante renal. La elevada  variabilidad farmacocinética de sirólimus hace que la monitorización  farmacocinética y la individualización posológica de la terapia inmunosupresora sea un proceso crucial para conseguir mejores resultados de  eficacia. La disponibilidad de un modelo farmacocinético poblacional permite  realizar un mejor ajuste farmacocinético de las concentraciones plasmáticas de  sirólimus y así conseguir un mayor beneficio clínico.Método: Se realizó un análisis sistemático de la literatura disponible en las  bases de datos Medline, Embase y Scopus para identificar y posteriormente analizar los modelos farmacocinéticos poblacionales de  irólimus administrado por vía oral en pacientes adultos con trasplante renal. Se utilizaron como descriptores MeSH: kidney transplantation, pharmacokinetic  y sirolimus. De cada artículo seleccionado se evaluó: la  población a estudio, el esquema de tratamiento inmunosupresor, los tiempos  de muestreo de las extracciones de sangre, las covariables analizadas, el tipo  de modelo farmacocinético, el programa informático utilizado, los parámetros  armacocinéticos estimados, la variabilidad interindividual de  los parámetros  farmacocinéticos, la variabilidad residual y las ecuaciones matemáticas del  modelo farmacocinético. RESULTADOS: Se obtuvieron un total de 548 resultados, excluyendo 175  registros tras identificarse en más de una base de datos. Finalmente se  seleccionaron siete artículos que cumplían los criterios de inclusión. La mayoría  de los modelos farmacocinéticos encontrados siguen un modelo  bicompartimental. Covariables como edad, peso, función hepática, exposición y  dosis de ciclosporina, dosis de sirólimus, polimorfismos genéticos del  CYP3A5, creatinina sérica y tratamiento concomitante explican la variabilidad  interindividual de sirólimus. CONCLUSIONES: El modelo bicompartimental fue el modelo farmacocinético de  elección en la mayoría de los estudios seleccionados. La variabilidad interindividual de los parámetros farmacocinéticos de sirólimus se explica por variables demográficas, clínicas, genéticas y bioquímicas. La disponibilidad de modelos farmacocinéticos de sirólimus permiten  ndividualizar la terapia en pacientes con trasplante renal.

Modelos farmacocinéticos poblacionales de sirólimus en pacientes trasplantados renales: Revisión sistemática / Population pharmacokinetics models of sirolimus in renal transplant patients: A systematic review

Objetivo: Sirólimus es un fármaco utilizado en los esquemas terapéuticos inmunosupresores en pacientes con trasplante renal. La elevada variabilidad farmacocinética de sirólimus hace que la monitorización farmacocinética y la individualización posológica de la terapia inmunosupresorasea un proceso crucial para conseguir mejores resultados de eficacia. Ladisponibilidad de un modelo farmacocinético poblacional permite realizar un mejor ajuste farmacocinético de las concentraciones plasmáticasde sirólimus y así conseguir un mayor beneficio clínico.Método: Se realizó un análisis sistemático de la literatura disponible enlas bases de datos Medline, Embase y Scopus para identificar y posteriormente analizar los modelos farmacocinéticos poblacionales de sirólimusadministrado por vía oral en pacientes adultos con trasplante renal. Seutilizaron como descriptores MeSH: kidney transplantation, pharmacokinetic y sirolimus. De cada artículo seleccionado se evaluó: la poblacióna estudio, el esquema de tratamiento inmunosupresor, los tiempos demuestreo de las extracciones de sangre, las covariables analizadas, eltipo de modelo farmacocinético, el programa informático utilizado, losparámetros farmacocinéticos estimados, la variabilidad interindividual de los parámetros farmacocinéticos, la variabilidad residual y las ecuacionesmatemáticas del modelo farmacocinético.Resultados: Se obtuvieron un total de 548 resultados, excluyendo175 registros tras identificarse en más de una base de datos. Finalmentese seleccionaron siete artículos que cumplían los criterios de inclusión.La mayoría de los modelos farmacocinéticos encontrados siguen unmodelo bicompartimental. Covariables como edad, peso, función hepática, exposición y dosis de ciclosporina, dosis de sirólimus, polimorfismosgenéticos del CYP3A5, creatinina sérica y tratamiento concomitante explican la variabilidad interindividual de sirólimus. (AU)

Objective: Sirolimus is used in the immunosuppressive therapeutictreatment of kidney transplant patients. The high pharmacokinetic variability of sirolimus makes pharmacokinetic monitoring and dosage individualization of immunosuppressive therapy a key process to achieve betterefficacy results. The availability of a population pharmacokinetic modelcan be used to provide better pharmacokinetic adjustment of plasma concentrations of sirolimus and thus achieve greater clinical benefit.Method: We conducted a systematic review of the literature availablein the Medline, Embase, and Scopus databases to identify and subsequently analyze population pharmacokinetic models of orally administered sirolimus in adult patients after kidney transplant. The descriptorsused MeSH were kidney transplantation, pharmacokinetics, and sirolimus.The following variables from the selected studies were assessed: studypopulation, immunosuppressive treatment, blood sampling times, covariates analyzed, type of pharmacokinetic model, computer software used,estimated pharmacokinetic parameters, interindividual variability of pharmacokinetic parameters, residual variability and mathematical equationsof the pharmacokinetic model. Results: A total of 548 results were obtained, excluding 175 records thatwere identified in more than one database. Finally, seven articles that met theinclusion criteria were selected. Most of the pharmacokinetic models foundfit a two-compartment model. The interindividual variability of sirolimus wasexplained by covariates such as age, weight, liver function, cyclosporineexposure and dose, sirolimus doses, CYP3A5 genetic polymorphisms, serumcreatinine, and concomitant treatment. (AU)