Proactive therapeutic drug monitoring and pharmacogenetic analysis in inflammatory bowel disease: A systematic review.

OBJECTIVE: The rise in the development of monoclonal antibodies has brought  about a revolution in the pharmacotherapy of inflammatory bowel disease  (Crohn's disease and ulcerative colitis). Systematic plasma concentrations monitoring of these biological drugs in anticipation of potential  clinical failures of treatment is known as proactive therapeutic drug  monitoring. New pharmacogenetic analysis techniques have recently been  developed that can predict response to these treatments even before they are administered. The goal of this systematic review is to analyze the potential benefits of proactive therapeutic drug monitoring and of the  harmacogenetic analysis of biological drugs in inflammatory bowel disease  patients in terms of clinical remission. METHOD: A systematic search was performed in the MEDLINE/Pubmed, Embase and Cochrane Library databases using the  escriptors proactive drug monitoring, biological drugs, inflammatory bowel  disease and pharmacogenetics. Only randomized clinical trials published  between January 2015 and May 2021 were included; all articles whose main  topic was not related to the topic were excluded by hand. The quality of the  articles  was assessed using the Jadad scale and risk of bias was assessed  using the Cochrane Collaboration tool. RESULTS: After applying inclusion and exclusion criteria, seven of the 228  retrieved articles were selected for review. Almost all the studies measured the  same clinical variables (Harvey-Bradshaw index for Crohn's disease and  Mayo score for ulcerative colitis). Only in two of the included studies was  proactive therapeutic drug monitoring superior to reactive monitoring- or no  level-guided dose adjustments. No pharmacogenetic analyses were found that  met the criteria defined. Conclusions: This review shows that the data  supporting the use of proactive therapeutic drug monitoring in inflammatory  bowel disease is limited and of low quality. Although pharmacogenetic analysis  can be a useful tool for personalizing treatment, further and better designed  randomized clinical trials are needed to determine the role of proactive drug monitoring strategies in clinical practice.

OBJETIVO: El auge del desarrollo de los anticuerpos monoclonales supuso una  revolución en la farmacoterapia de la enfermedad inflamatoria intestinal,  principalmente enfermedad de Crohn y colitis ulcerosa. La monitorización de  niveles plasmáticos de estos fármacos biológicos de forma programada y  anticipada a un posible fracaso clínico del tratamiento se conoce como  monitorización farmacocinética proactiva. Además, recientemente se han  puesto a punto nuevas técnicas para el análisis farmacogenético que pueden  predecir la respuesta a estos tratamientos, incluso antes de ser administrados.  El objetivo de esta revisión sistemática es analizar los posibles beneficios de la  monitorización proactiva y del análisis farmacogenético de fármacos biológicos  en pacientes con enfermedad inflamatoria intestinal en términos de remisión  clínica.Método: Se buscó en las bases de datos Medline/PubMed, Embase y Cochrane  Library con los descriptores "Proactive drug monitoring",  biological drugs", "inflammatory bowel disease" y "pharmacogenetics". Se  incluyeron únicamente ensayos clínicos aleatorizados publicados entre enero de 2015 y mayo de 2021, y se excluyeron las publicaciones cuyo  tema principal no era el de la búsqueda. La calidad de los artículos se evaluó  mediante la escala de Jadad y además se evaluaron los riesgos de sesgo por la herramienta de la Colaboración Cochrane. RESULTADOS: Tras aplicar los criterios de inclusión y exclusión, se seleccionaron para la revisión 7 de las 228 referencias recuperadas. Casi todos  los estudios coincidían en las variables clínicas medidas (índice de Harvey- Bradshaw en enfermedad de Crohn e índice de Mayo en colitis ulcerosa). Sólo  en dos de los estudios incluidos la monitorización proactiva era superior a la  reactiva o al no realizar ajustes de dosis guiados por niveles. No se  encontraron ensayos clínicos con los criterios de búsqueda definidos acerca del  análisis farmacogenético. CONCLUSIONES: Esta revisión muestra que los datos que apoyan el uso de la  monitorización farmacocinética proactiva en enfermedad inflamatoria intestinal  son limitados y de baja calidad. El análisis  armacogenético puede ser una herramienta útil para ofrecer a los pacientes el  tratamiento más personalizado, pero son necesarios más ensayos clínicos  aleatorizados con mejor diseño para determinar el lugar de estas estrategias  en la práctica clínica.

Monitoring coagulation factors during surgery. A systematic review.

OBJECTIVE: The management of surgeries in patients with hemophilia is  complex and requires adequate clotting factor adjustment to avoid bleeding  complications and excessive factor consumption. The aim of this systematic  review is to analyze the pharmacokinetic studies published on surgery in  hemophilic patients, the methodologies used, the main pharmacokinetic covariates applied, and the recommendations made by clinical guidelines. METHOD: A structured search was performed in Pubmed, the Cochrane Library,  and the Database of Abstracts of Reviews of Effects using the search terms  hemophilia (or haemophilia), surgery and pharmacokinetics (or PK). No date or  language limits were established. Results: The search yielded 186 results, from which 34 articles were selected.  Many of these analyzed the use of continuous infusions with the aim of  achieving stable factor VIII or IX levels and reducing overall factor  consumption. However, continuous infusions have fallen into disuse. For  decades, clinical guidelines have recommended the performance of comprehensive pharmacokinetic studies prior to surgery (9-11 samples). The clearance rate obtained is used to adjust the presurgical factor  dose (or the infusion rate in case of continuous perfusion). Another approach is the use of population pharmacokinetic models, which allow adjustments to  be made based on a more limited number of samples. However, the validity of  these presurgical pharmacokinetic estimates ceases as soon as the surgical  procedure is initiated, making it necessary to adjust the dose based on periodic  peak and trough levels. In addition, depending on the  type of  surgery, clinical guidelines recommend maintaining factor VIII and IX levels  above specific thresholds for certain periods of time, which makes it essential  to use pharmacokinetics during the pre- and post-surgical process. In recent  years, specific factor VIII and factor IX pharmacokinetic population models  have been developed for surgery. The main covariates of these population  pharmacokinetic models are age, blood type, and type of surgery for factor  VIII; and age and body weight for factor IX. CONCLUSIONS: Pharmacokinetic estimation could allow individual and standardized intraoperative dose adjustments to be conducted in patients with hemophilia. The development of specific population  pharmacokinetic models for surgery, including those based on extended half- life factors, will allow an optimization of current treatments, potentially  reducing factor consumption and hospital stays.

OBJETIVO: El manejo de las cirugías en pacientes hemofílicos es complejo y  requiere de un ajuste adecuado de los factores de coagulación para evitar  complicaciones hemorrágicas y un consumo elevado. El objetivo de esta  revisión sistemática es analizar los estudios farmacocinéticos publicados en  cirugía en pacientes con hemofilia, las metodologías empleadas, las principales  covariables farmacocinéticas y las recomendaciones de las guías  clínicas.Método: Se ha realizado una búsqueda estructurada sin restricciones de fecha  ni idioma en Pubmed, Cochrane y Database of Abstracts of Reviews of  Effects empleado los mismos términos de búsqueda: (hemophilia or  haemophilia), surgery y (pharmacokinetics or PK). Resultados: La búsqueda sistemática obtuvo 186 resultados, de los que seleccionamos 34 artículos. Muchos estudios analizaban el uso de  erfusiones continuas con el objetivo de lograr niveles estables de factor VIII o  IX y reducir el consumo global, aunque su empleo ha caído en desuso. Durante  décadas las guías clínicas recomendaban realizar estudios  farmacocinéticos completos previos a la cirugía (9-11 muestras), según los  cuales se ajusta la dosis prequirúrgica, así como la velocidad de infusión en caso de perfusión continua basándose en el aclaramiento calculado. Otra aproximación es el empleo de modelos poblacionales farmacocinéticos, ajustando con un número más limitado de muestras. Estas  estimaciones farmacocinéticas prequirúrgicas pierden validez tan pronto como  se inicia un procedimiento quirúrgico, y tienen que ajustarse con niveles pico y valle periódicos. Además, las guías clínicas recomiendan, en función del  populationtipo de cirugía, mantener los niveles de factores VIII y IX por  encima de los umbrales específicos durante periodos, por lo que resulta  fundamental emplear la farmacocinética durante el proceso pre y  postquirúrgico. En los últimos años se han desarrollado modelos poblacionales  farmacocinéticos de factores VIII y IX específicos para cirugía. Las principales  covariables de estos modelos son la edad, el grupo sanguíneo y el tipo de  cirugía para el factor VIII, y la edad y el peso corporal para el factor IX. CONCLUSIONES: La farmacocinética puede permitir ajustar de forma individual y  protocolizada las cirugías en pacientes hemofílicos. El desarrollo de modelos farmacocinéticos poblacionales específicos para cirugía, incluyendo los factores de vida media extendida, permitirá optimizar estos tratamientos, con potencial reducción del consumo y las  estancias hospitalarias.

Monitorización farmacocinética proactiva y análisis farmacogenético en la enfermedad inflamatoria intestinal: Revisión sistemática / Proactive therapeutic drug monitoring and pharmacogenetic analysis in inflammatory bowel disease: A systematic review

Objetivo: El auge del desarrollo de los anticuerpos monoclonalessupuso una revolución en la farmacoterapia de la enfermedad inflamatoria intestinal, principalmente enfermedad de Crohn y colitis ulcerosa. Lamonitorización de niveles plasmáticos de estos fármacos biológicos deforma programada y anticipada a un posible fracaso clínico del tratamiento se conoce como monitorización farmacocinética proactiva. Además, recientemente se han puesto a punto nuevas técnicas para el análisisfarmacogenético que pueden predecir la respuesta a estos tratamientos,incluso antes de ser administrados. El objetivo de esta revisión sistemáticaes analizar los posibles beneficios de la monitorización proactiva y delanálisis farmacogenético de fármacos biológicos en pacientes con enfermedad inflamatoria intestinal en términos de remisión clínica.Método: Se buscó en las bases de datos Medline/PubMed, Embase yCochrane Library con los descriptores “Proactive drug monitoring”, “biological drugs”, “inflammatory bowel disease” y “pharmacogenetics”. Seincluyeron únicamente ensayos clínicos aleatorizados publicados entreenero de 2015 y mayo de 2021, y se excluyeron las publicaciones cuyo tema principal no era el de la búsqueda. La calidad de los artículos seevaluó mediante la escala de Jadad y además se evaluaron los riesgosde sesgo por la herramienta de la Colaboración Cochrane.Resultados: Tras aplicar los criterios de inclusión y exclusión, se seleccionaron para la revisión 7 de las 228 referencias recuperadas. Casitodos los estudios coincidían en las variables clínicas medidas (índice deHarvey-Bradshaw en enfermedad de Crohn e índice de Mayo en colitisulcerosa). Sólo en dos de los estudios incluidos la monitorización proactiva era superior a la reactiva o al no realizar ajustes de dosis guiados porniveles. No se encontraron ensayos clínicos con los criterios de búsquedadefinidos acerca del análisis farmacogenético. (AU)

Objective: The rise in the development of monoclonal antibodies hasbrought about a revolution in the pharmacotherapy of inflammatory boweldisease (Crohn’s disease and ulcerative colitis). Systematic plasma concentrations monitoring of these biological drugs in anticipation of potentialclinical failures of treatment is known as proactive therapeutic drug monitoring. New pharmacogenetic analysis techniques have recently been developed that can predict response to these treatments even before they areadministered. The goal of this systematic review is to analyze the potentialbenefits of proactive therapeutic drug monitoring and of the pharmacogenetic analysis of biological drugs in inflammatory bowel disease patientsin terms of clinical remission.Method: A systematic search was performed in the MEDLINE/Pubmed,Embase and Cochrane Library databases using the descriptors proactivedrug monitoring, biological drugs, inflammatory bowel disease and pharmacogenetics. Only randomized clinical trials published between January2015 and May 2021 were included; all articles whose main topic wasnot related to the topic were excluded by hand. The quality of the articles was assessed using the Jadad scale and risk of bias was assessed usingthe Cochrane Collaboration tool.Results: After applying inclusion and exclusion criteria, seven of the228 retrieved articles were selected for review. Almost all the studiesmeasured the same clinical variables (Harvey-Bradshaw index for Crohn’sdisease and Mayo score for ulcerative colitis). Only in two of the included studies was proactive therapeutic drug monitoring superior to reactivemonitoring- or no level-guided dose adjustments. No pharmacogeneticanalyses were found that met the criteria defined. (AU)

Monitorización de factores de la coagulación en cirugía. Revisión sistemática / Monitoring coagulation factors during surgery. A systematic review

Objetivo: El manejo de las cirugías en pacientes hemofílicos es complejo y requiere de un ajuste adecuado de los factores de coagulaciónpara evitar complicaciones hemorrágicas y un consumo elevado. El objetivo de esta revisión sistemática es analizar los estudios farmacocinéticos publicados en cirugía en pacientes con hemofilia, las metodologíasempleadas, las principales covariables farmacocinéticas y las recomendaciones de las guías clínicas.Método: Se ha realizado una búsqueda estructurada sin restriccionesde fecha ni idioma en Pubmed, Cochrane y Database of Abstracts ofReviews of Effects empleado los mismos términos de búsqueda: (hemophilia or haemophilia), surgery y (pharmacokinetics or PK).Resultados: La búsqueda sistemática obtuvo 186 resultados, de los queseleccionamos 34 artículos. Muchos estudios analizaban el uso de perfusiones continuas con el objetivo de lograr niveles estables de factor VIIIo IX y reducir el consumo global, aunque su empleo ha caído en desuso.Durante décadas las guías clínicas recomendaban realizar estudios farmacocinéticos completos previos a la cirugía (9-11 muestras), según los cualesse ajusta la dosis prequirúrgica, así como la velocidad de infusión encaso de perfusión continua basándose en el aclaramiento calculado. Otraaproximación es el empleo de modelos poblacionales farmacocinéticos,ajustando con un número más limitado de muestras. Estas estimacionesfarmacocinéticas prequirúrgicas pierden validez tan pronto como se iniciaun procedimiento quirúrgico, y tienen que ajustarse con niveles pico yvalle periódicos. (AU)

Objective: The management of surgeries in patients with hemophiliais complex and requires adequate clotting factor adjustment to avoidbleeding complications and excessive factor consumption. The aim of thissystematic review is to analyze the pharmacokinetic studies published onsurgery in hemophilic patients, the methodologies used, the main pharmacokinetic covariates applied, and the recommendations made by clinicalguidelines.Method: A structured search was performed in Pubmed, the CochraneLibrary, and the Database of Abstracts of Reviews of Effects using thesearch terms hemophilia (or haemophilia), surgery and pharmacokinetics(or PK). No date or language limits were established.Results: The search yielded 186 results, from which 34 articles wereselected. Many of these analyzed the use of continuous infusions withthe aim of achieving stable factor VIII or IX levels and reducing overallfactor consumption. However, continuous infusions have fallen into disuse.For decades, clinical guidelines have recommended the performance ofcomprehensive pharmacokinetic studies prior to surgery (9-11 samples).The clearance rate obtained is used to adjust the presurgical factor dose(or the infusion rate in case of continuous perfusion). Another approach isthe use of population pharmacokinetic models, which allow adjustmentsto be made based on a more limited number of samples. However, thevalidity of these presurgical pharmacokinetic estimates ceases as soon asthe surgical procedure is initiated, making it necessary to adjust the dosebased on periodic peak and trough levels. (AU)

Intraperitoneal vancomycin in neonates during peritoneal dialysis: A case report.

WHAT IS KNOWN AND OBJECTIVE: Guidelines for prevention and treatment of peritonitis in paediatric patients recommend vancomycin. We present the clinical practice in neonates during peritoneal dialysis and evaluate dosage and serum levels of vancomycin. CASE SUMMARY: This case report describes a newborn with acute renal failure under continuous peritoneal dialysis therapy and intraperitoneal vancomycin. We report the treatment dosage and serum vancomycin levels. WHAT IS NEW AND CONCLUSION: There is great variability in the recommended dose of vancomycin for continuous peritoneal dialysis and the available clinical experience. Further investigation of dosing in children particularly in newborns, especially in loading dose, is necessary.

Experiencia en el manejo de inmunosupresores con los fármacos inhibidores de proteasa frente al virus de la hepatitis C / Experience in the management of immunosuppressant treatment with hepatitis C virus protease inhibitors

INTRODUCCIÓN: Los fármacos antivirales frente al virus de la hepatitis C (VHC) presentan un número importante de interacciones. El objetivo de este estudio es describir la interacción de telaprevir, boceprevir y sofosbuvir con los fármacos inmunosupresores en pacientes trasplantados. Métodos :Estudio observacional retrospectivo de pacientes trasplantados hepáticos con infección por VHC que iniciaron tratamiento con telaprevir, boceprevir o sofosbuvir. Se recogieron las dosis, pautas posológicas y niveles plasmáticos de tacrolimus, ciclosporina y sirolimus previas y posteriores al inicio del tratamiento antiviral. Se calculó la variación media de dosis e intervalo de dosificación, así como la modificación de los niveles de inmunosupresor tras iniciar el tratamiento. RESULTADOS: Se incluyeron 35 pacientes. En pacientes tratados con telaprevir (n = 18), la dosis de ciclosporina se redujo una media de 59,1% (SD = 14,6%), obteniéndose una reducción media de 14,6% (18,8%) en los niveles plasmáticos. En cuanto a tacrolimus, la dosis se redujo en un 34,3% (31,7%) aumentando el intervalo de dosificación una media de 73,4 (38,2) horas. Con ello, los niveles se incrementaron un 59,7% (89,6%). En los pacientes tratados con boceprevir (n = 4), tacrolimus se inició con una reducción del 18,1% (9,8%) de la dosis inicial y un aumento medio en el intervalo de dosificación de 12,0 (16,9) horas, observándose una reducción media del 37,7% (21,8%) en los niveles plasmáticos. El tratamiento con sofosbuvir (n = 13) no mostró variaciones importantes en los niveles de inmunosupresores. CONCLUSIONES: La interacción de telaprevir y boceprevir con los fármacos inmunosupresores requiere un ajuste de la dosis previa de los mismos al inicio del tratamiento, así como una monitorización rigurosa de sus niveles plasmáticos

INTRODUCTION: Antiviral drugs for the treatment of hepatitis C virus (HCV) infections have a large number of interactions. The aim of this study was to describe the interactions of telaprevir, boceprevir and sofosbuvir with immunosuppressive drugs in liver transplant recipients. METHODS: A retrospective observational study was performed in liver transplant patients with HCV infection who started treatment with telaprevir, boceprevir or sofosbuvir. Dose, regimens and plasma levels of tacrolimus, cyclosporine and sirolimus before and after antiviral treatment initiation were collected. Average variations in dose, dosing interval and immunosuppressive plasma levels after the start of treatment were calculated. RESULTS: Thirty-five patients were included. In patients treated with telaprevir (n = 18), the cyclosporine dose was reduced by an average of 59.1% (SD = 14.6%), yielding an average reduction of 14.6% (18.8%) in plasma levels. The dose of tacrolimus was reduced by 34.3% (31.7%), increasing the dosing interval by a mean of 73.4 (38.2) hours. After this variation, tacrolimus levels were increased by an average of 59.7% (89.6%). In patients treated with boceprevir (n = 4), tacrolimus started with a reduction of 18.1% (9.8%) of the initial dose and an average increase in the dosing interval of 12.0 (16.9) hours, showing a mean reduction in plasma levels of 37.7% (21.8%). Sofosbuvir therapy (n = 13) showed no significant variations in immunosuppressive drug levels. CONCLUSIONS: The interaction of telaprevir and boceprevir with immunosuppressive drugs requires a substantial dose reduction at the beginning of treatment and close monitoring of plasma levels

[Experience in the management of immunosuppressant treatment with hepatitis C virus protease inhibitors]. / Experiencia en el manejo de inmunosupresores con los fármacos inhibidores de proteasa frente al virus de la hepatitis C.

INTRODUCTION: Antiviral drugs for the treatment of hepatitis C virus (HCV) infections have a large number of interactions. The aim of this study was to describe the interactions of telaprevir, boceprevir and sofosbuvir with immunosuppressive drugs in liver transplant recipients. METHODS: A retrospective observational study was performed in liver transplant patients with HCV infection who started treatment with telaprevir, boceprevir or sofosbuvir. Dose, regimens and plasma levels of tacrolimus, cyclosporine and sirolimus before and after antiviral treatment initiation were collected. Average variations in dose, dosing interval and immunosuppressive plasma levels after the start of treatment were calculated. RESULTS: Thirty-five patients were included. In patients treated with telaprevir (n = 18), the cyclosporine dose was reduced by an average of 59.1% (SD = 14.6%), yielding an average reduction of 14.6% (18.8%) in plasma levels. The dose of tacrolimus was reduced by 34.3% (31.7%), increasing the dosing interval by a mean of 73.4 (38.2) hours. After this variation, tacrolimus levels were increased by an average of 59.7% (89.6%). In patients treated with boceprevir (n = 4), tacrolimus started with a reduction of 18.1% (9.8%) of the initial dose and an average increase in the dosing interval of 12.0 (16.9) hours, showing a mean reduction in plasma levels of 37.7% (21.8%). Sofosbuvir therapy (n = 13) showed no significant variations in immunosuppressive drug levels. CONCLUSIONS: The interaction of telaprevir and boceprevir with immunosuppressive drugs requires a substantial dose reduction at the beginning of treatment and close monitoring of plasma levels.

Drug Interaction Between Oral Cyclosporine Modified and Iron.

OBJECTIVE: To describe a recent case of suspected interaction between oral cyclosporine modified and iron. CASE SUMMARY: A 33-year-old man underwent urgent cardiac transplantation for refractory cardiogenic shock caused by acute myocarditis. The patient had persistently low levels of cyclosporine despite a dose increase of the drug after the change of administration route from intravenous to oral. Spacing the administration of cyclosporine modified from oral iron resolved the problem. This drug interaction was reported as "probable" as determined by a Drug Interaction Probability Scale score of 7. Using this scoring system, the patient experienced a probable drug interaction between cyclosporine and iron both administered orally, and we surmise that the mechanism is that iron physicochemically destabilizes the cyclosporine microemulsion when both are administered concurrently. DISCUSSION: This may be because of the interaction between cyclosporine microemulsion and iron because this cation can destabilize the immunosuppressant dosage form. CONCLUSIONS: Taking into account that joint administration of oral iron and cyclosporine modified can generate a physicochemical interaction that involves a decrease in the absorption of cyclosporine modified, we believe that it is necessary to recommend spacing administrations of both drugs as well as monitoring levels of cyclosporine in order to ensure optimal levels of immunosuppression.

Population pharmacokinetic analysis of vancomycin in neonates. A new proposal of initial dosage guideline.

AIM: To determine the population pharmacokinetic parameters of vancomycin in neonatal patients with a wide range of gestational age and birth weight, and subsequently to design an initial dosing schedule for vancomycin in neonates. METHODS: Using nonlinear mixed-effects modelling (NONMEM VI), the pharmacokinetics of vancomycin were investigated in 70 neonates with postmenstrual age and body weight ranging 25.1-48.1 weeks and 0.7-3.7kg, respectively. A one-compartment linear disposition model with zero order input and first-order elimination was used to describe the data. Nine demographic characteristics and 21 co-administered drugs were evaluated as covariates of clearance (CL) and distribution volume (V(d) ) of vancomycin. RESULTS: Weight-normalized clearance of vancomycin was influenced by postmenstrual age (PMA) and co-administration of amoxicillin-clavulanic acid. Weight-normalized volume of distribution was influenced by co-administration of spironolactone. CL and V(d) of the typical individual in this study population (PMA = 34.6 weeks, weight = 1.7kg) were estimated to be 0.066lh(-1) kg(-1) (95% CI 0.059, 0.073lh(-1) kg(-1) ) and 0.572lkg(-1) (95% CI 0.505, 0.639lkg(-1) ), respectively. This model was used to predict a priori serum vancomycin concentrations in a validation group (n= 41), which were compared with observed concentrations to determine the predictive performance of the model. The 95% confidence interval of mean prediction error included zero for both peak and trough vancomycin concentrations. CONCLUSIONS: Postmenstrual age, co-administration of amoxicillin-clavulanic acid and spironolactone have a significant effect on the weight-normalized CL and V(d) . An initial dosage guideline for vancomycin is proposed for preterm and full-term neonates, whereas the population pharmacokinetic model can be used for dosage individualization of vancomycin.