Hospitalization budget impact during the COVID-19 pandemic in Spain.

OBJECTIVES: The aim was to determine the direct impact of the COVID-19 pandemic on Spain's health budget. METHODS: Budget impact analyses based on retrospective data from patients with suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) admitted to a Spanish hospital between February 26 and May 21, 2020. Direct medical costs from the perspective of the hospital were calculated. We analyzed diagnostic tests, drugs, medical and nursing care, and isolation ward and ICU stays for three cohorts: patients seen in the emergency room only, hospitalized patients who tested positive for SARS-CoV-2, and patients who tested negative. RESULTS: The impact on the hospital's budget for the 3 months was calculated at €15,633,180, 97.4% of which was related to health care and hospitalization. ICU stays accounted for 5.3% of the total costs. The mean cost per patient was €10,744. The main costs were staffing costs (10,131 to 11,357 €/patient for physicians and 10,274 to 11,215 €/patient for nurses). Scenario analysis showed that the range of hospital expenditure was between €14,693,256 and €16,524,924. The median impact of the pandemic on the Spanish health budget in the sensitivity analysis using bootstrapped individual data was €9357 million (interquartile range [IQR], 9071 to 9689) for the conservative scenario (113,588 hospital admissions and 11,664 ICU admissions) and €10,385 million (IQR, 110,030 to 10,758) for the worst-case scenario (including suspected cases). CONCLUSION: The impact of COVID-19 on the Spanish public health budget (12.3% of total public health expenditure) is greater than multiple sclerosis, cancer and diabetes cost.

Exploratory analysis for the implementation of antineoplastic logarithmic dose banding.

Background Dose banding (DB) is a strategy to rationalise antineoplastic production at Hospital Pharmacy Aseptic Compounding Units (ACUs) and to reduce patient's waiting time. DB allows for optimizing workflows and workloads, facilitating adoption of new technologies, and increasing safety, quality and efficiency of the compounding process. Objective To evaluate the potential impact of implementation of Logarithmic DB and to identify antineoplastic agents and preparations that fulfil criteria published and establish the number and standard doses that could be compounded in advance at the ACU. Setting University and Polytechnic third level general hospital. Method Retrospective observational study (December 2015-May 2016). Antineoplastic dose production was analysed. Investigational drugs were excluded. Three criteria were applied following bibliography reviewed to select candidates to be compounded at our ACU as standardised using logarithmic DB: (a) Antineoplastic preparations > 250 per year; (b) psychochemical stability in optimal storage conditions at least 14 days; (c) maximum five logarithmic standardised doses that include at least 60% of all individualised doses compounded for a given drug. Main outcome measure Number of antineoplastic agents, preparations and logarithmic standard doses candidates to DB. Results 15,436 antineoplastic individualised doses corresponding to 69 antineoplastic agents were analysed. At our institution applying selection criteria, 19 (27%) antineoplastic drugs (3 monoclonal antibodies, 16 cytotoxic) were potential candidates to DB. 6285 (40%) of compounded individualised dose preparations could be prepared in 84 logarithmic standard doses in advance. Conclusion Dose banding implementations could contribute to rationalise antineoplastic production and increase the ACUs compounding capacity.

Pilot evaluation of home delivery programme in haemophilia.

WHAT IS KNOWN AND OBJECTIVES: Most of the clotting factor (CF) dispensations to haemophiliac patients are centralized in a few haemophilia treatment centres, necessitating frequent visits and long travel distances. The aim was to evaluate the home delivery programme developed by the Outpatient Pharmaceutical Care Unit (OPCU) through the association of patients (ASHECOVA). METHODS: A specific software programme was designed to communicate the individual CF requirements. Dispensations were prepared in advance, and an ASHECOVA member collected and delivered to patients' homes in optimal conditions. Data regarding the programme were analysed from December 2011 to December 2017. An electronic satisfaction survey with 34 questions was conducted, asking about organizational aspects, education and communication, use of apps and satisfaction level. RESULTS AND DISCUSSION: Forty-nine patients were included and 2464 home deliveries were made, without any reported incident related to dispensation errors, drug preservation, communication or confidentiality problems. This system avoids 11.4 annual dispensation visits per patient to OCPU, and a mean travel distance, time and cost of 1189.1 km, 945.3 minutes and 373.5 euros, respectively. Overall satisfaction with home delivery was 9.7, without any change suggested in the current system. Ninety-five per cent of individuals believed that the programme improves adherence and all patients would recommend it to other patients. The most common benefits reported were less frequent visits to hospital, reducing time and cost spent on transportation. WHAT IS NEW AND CONCLUSION: The home delivery programme guarantees a proper follow-up of treatments with full patient satisfaction. This programme allows OPCU to achieve better pharmaceutical care, traceability of the process and optimization of working times and CF stock management.

Antimicrobial stewardship programme in critical care medicine: A prospective interventional study.

OBJECTIVE: Hospital antimicrobial stewardship programmes have achieved savings and a more rational use of antimicrobial treatments in general wards. The purpose of this report is to evaluate the experience of an antimicrobial stewardship programme in an intensive care unit (ICU). DESIGN: Prospective interventional, before-and-after study. SCOPE: 24-bed medical ICU in a tertiary hospital. INTERVENTION: Prospective audit and feedback antimicrobial stewardship programme. ENDPOINTS: Antimicrobial consumption, antimicrobial related costs, multi-drug resistant microorganisms (MDRM) prevalence, nosocomial infections incidence, ICU length of stay, and ICU mortality rates were compared before and after one-year intervention. RESULTS: A total of 218 antimicrobial episodes of 182 patients were evaluated in 61 team meetings. Antimicrobial stewardship suggestions were accepted in 91.5% of the cases. Total antimicrobial DDD/100 patient-days consumption was reduced from 380.6 to 295.2 (-22.4%; p=0.037). Antimicrobial stewardship programme was associated with a significant decrease in the prescription of penicillins plus b-lactamase inhibitors, linezolid, cephalosporins, and aminoglycosides. Overall antimicrobial spending was reduced by €119,636. MDRM isolation and nosocomial infections per 100 patient-days did not change after the intervention period. No changes in length of stay or mortality rate were observed. CONCLUSIONS: An ICU antimicrobial stewardship programme significantly reduced antimicrobial use without affecting inpatient mortality and length of stay. Our results further support the implementation of an antimicrobial stewardship programme in critical care units.

Aflibercept in exudative age related macular degeneration refractory to ranibizumab.

PURPOSE: The aim of this study is to determine the effectiveness, safety and cost of aflibercept in the treatment of wet age-related macular degeneration (ARMD) refractory to ranibizumab. METHODS: Retrospective observational study was conducted on patients diagnosed with wet ARMD, and previously treated with ranibizumab. Efficacy variables assessed were changes in visual acuity (BCVA) and anatomical improvements in the most affected eye. Factors associated with improvement of BCVA with aflibercept were also studied. Adverse events related to the aflibercept administration were recorded. Cost analysis data were collected from the hospital perspective, and only taking the direct medical costs into account. Cost-effectiveness analysis was calculated using the aflibercept treatment cost, and effectiveness calculated as BCVA gained. RESULTS: A total of 50 eyes corresponding to 46 patients were included. The median follow-up period was 4.6 months (range: 1.0-6.0). Improvement in visual acuity after the first 2 doses and at the end of the follow-up period was observed in 32.0 and 28.0% of treated eyes, respectively. None of the variables studied was associated with an improvement in the BCVA after treatment. No significant differences were found in the average monthly cost between treatments. CONCLUSIONS: Aflibercept is shown to be an effective treatment in a significant number of patients resistant to treatment with ranibizumab, presenting a cost similar to that generated during the final stages of treatment with ranibizumab.

Trans-arterial chemoembolization with doxorubicin-eluting particles versus conventional trans-arterial chemoembolization in unresectable hepatocellular carcinoma: A study of effectiveness, safety and costs.

OBJECTIVES: To compare the effectiveness, survival and cost in patients with unresectable hepatic cell carcinoma (HCC) treated with trans-arterial chemoembolization using doxorubicin-eluting beads (DEB-TACE) versus conventional TACE (cTACE) in clinical practice. MATERIAL AND METHODS: This single-centered retrospective observational study compared 60 consecutive HCC unresectable patients: 30 were treated with DEB-TACE and 30 used cTACE. Comparisons were with χ(2) test, Student t-test, and Kaplan Meier method. RESULTS: Of the 60 patients with HCC in non-curative stage, baseline characteristics were similar for both groups of treatment, and of these we observed lower survival in male patients and those who had hepatitis C virus (p=0.014 and p=0.003, respectively). No statistically significant differences were observed as a function of treatment employed with respect to overall survival (OS) at 5 years (29.99 months; 95%CI: 21.38-38.60 versus 30.67 months; 95%CI:22.65-38.70; p=0.626) and progression free survival (PFS) median of 11.57 months (95%CI: 0.97-22.18) versus 12.80 months (95%CI:0.00-32.37; p=0.618). The median length of hospital admission were 2.6 and 5.4 days (p<0.001) for DEB(-)TACE and cTACE, respectively. Toxicities grade 2-4 were higher in cTACE group (54 versus 31; p<0.001). The cost of the treatment was 1581 € for DEB(-)TACE and 514.63 € for cTACE. The overall mean cost of intervention was 3134 € and 3694.35 €, respectively (p=0.173). CONCLUSIONS: Chemoembolization in patients with unresectable HCC achieved OS close to 30 months at 5 years, independent of the technique employed. Similar overall costs but better tolerance of the DEB-TACE justified the higher costs of the procedure.

Clinical evaluation of rituximab treatment for neuromyelitis optica.

INTRODUCTION: Neuromyelitis optica is an inflammatory and usually relapsing demyelinating autoimmune disease of the central nervous system that targets the optic nerves and spinal cord. Rituximab has been used for different neurological diseases that are probably immune-mediated or involving humoural immunity. The objective of this study is to evaluate the efficacy and safety of rituximab as treatment for neuromyelitis optica in a tertiary hospital. METHODS: Retrospective study of patients with neuromyelitis optica treated with rituximab 1000mg on days 1 and 15, repeated every 6 to 8 months. We recorded EDSS score, relapse rate, overall condition, CD19+ count, presence of anti-NMO antibodies, and possible adverse reactions. RESULTS: Six patients were treated; all were women with a median age of 46 years (range, 38-58). Anti-NMO antibodies were detected in 3 patients (50%). Baseline EDSS was 4 (range 2.0-5.5). Two patients had previously been treated with an immunomodulatory drug. Median time from the first rituximab infusion to first relapse was 3.7 years (range 1.7-6.9). Two patients had infusion reactions after the first dose of rituximab. Four patients remained relapse-free and their EDSS score did not progress during rituximab treatment, one patient showed no clinical improvement, and one patient could not be evaluated. CONCLUSION: Rituximab can be considered an attractive therapeutic alternative for patients with neuromyelitis optica as there are no approved treatments for this disease. Further studies with rituximab are needed to establish the role of this drug in treating neuromyelitis optica.

[Analysis of the causes leading to withdrawal of the treatment with triple antiviral therapy for hepatitis C patients]. / Análisis de las causas de suspensión de tratamiento con triple terapia antiviral en pacientes con hepatitis C.

OBJECTIVE: To assess causes of suspension of hepatitis C treatment in patients receiving triple antiviral therapy (peginterferon+ ribavirin + protease inhibitor). METHODS: Retrospective observational study of patients who received triple antiretroviral therapy against hepatitis C between January 2012 - March 2013 and discontinued their treatment. RESULTS: Of 156 patients who initiated therapy, 41 discontinued treatment: Nineteen due to adverse events, being dermatological events in seven patients ( 36.8 %), intolerance in six(31.6%) and hematologic toxicity in four (15.8%) . Sixteen patients discontinued treatment for being ineffectiveness.Patients with higher inefficacy failure rate were "null-responders"(32.3% ) while the group of "relapsers" were the one with the highest rate of toxicity suspensions (15.6%). Two patients died during treatment for pneumonia. CONCLUSIONS: Triple therapy with boceprevir and telaprevir is associated with a significant number of treatment failures due to toxicity and ineffectiveness.

Objetivo: Evaluar las causas de suspensión de tratamientofrente a Hepatitis C que reciben triple terapia antiviral (peginterferon+ ribavirina + inhibidor de proteasa).Métodos: Estudio observacional retrospectivo de pacientes queiniciaron triple terapia antiviral entre enero 2012 - marzo 2013y suspendieron el tratamiento antes de completar el mismo.Resultados: De 156 pacientes que iniciaron triple terapia, 41interrumpieron el tratamiento: Diecinueve por toxicidad, siendodermatológica en siete pacientes (36,8%), intolerancia en seis(31,6%) y hematológica en cuatro (15,8%). Dieciséis pacientessuspendieron todo el tratamiento por ineficacia. El grupo depacientes con mayor porcentaje de fracasos por ineficacia fueronlos "no respondedores" (32,3%) mientras que el grupo depacientes "recidivantes" fueron el grupo con mayor porcentajede suspensiones por toxicidad (15,6%). Dos pacientes fallecierondurante el tratamiento por neumonía.Conclusiones: La triple terapia frente a VHC está asociada a unnúmero importante de fracasos terapéuticos tanto por toxicidadcomo por ineficacia.

Anidulafungin-induced alopecia.

OBJETIVE: To report a case of a woman in whom alopecia appeared after several months of treatment with anidulafungin. CASE SUMMARY: A 34-year-old woman with chronic femoral osteomyelitis with the presence of persistent suppuration, developed a Candida albicans infection, isolated in the fistula exudate cultures. After initial failures of single therapy with azoles, it was decided to administer fluconazole and anidulafungin 100 mg/d. One month after starting the treatment, the patient mentioned a greater hair loss than usual. At 3 months, the patient stopped taking the drug on noting the loss and easy falling out of her hair, with alopecia plaques 1 to 2 cm in size. At 2 months after stopping the anidulafungin, it was decided to restart combined antifungal treatment using micafungin and fluconazole; there was no mention of new or greater loss of hair. It was decided to change micafungin to anidulafungin again 90 days after starting treatment. In the first month of treatment, there appeared to be a reactivation in hair loss that later stabilized and improved. DISCUSSION: Drug-induced hair loss is an adverse reaction that has been identified during different hair growth phases. It has been described for the azoles group and has not been associated with candins until now. Results of the causality analysis, using the probability scale established by Naranjo, found the relationship as probable. CONCLUSIONS: Anidulafungin could be associated with hair loss. Physicians must be aware of this adverse effect in order to approach it properly and to detect possible nonadherence to treatment.

[Boceprevir and telaprevir utilization: evaluation for the treatment of chronic hepatitis C]. / Estudio de utilización de boceprevir y telaprevir para el tratamiento de la hepatitis C crónica.

INTRODUCTION: Protease inhibitors, boceprevir and telaprevir, have changed the treatment paradigm of chronic hepatitis C (CHC). The objective is analyzing the degree of compliance with the recommendations for boceprevir and telaprevir use that have been issued for the Spanish Agency for Medicines and Health Products in patients with CHC on a tertiary hospital. METHOD: All patients who started treatment with triple therapy between March and September 2012 were included. Compliance the initiation criteria were assessed and whether the rules of discontinuation due to ineffectiveness were made. RESULTS: 76 patients, 24 treated with boceprevir and 52 with telaprevir were included. In 11 patients (14.5%) triple therapy was initiated without keeping the Spanish Agency criteria, 6 were monoinfected patients and 4 with liver transplantation. In the group of boceprevir viral load (VL) at 12th week of treatment in 19 patients was measured (79.2%) and in 13 patients at 24th week (61.9 %). For telaprevir VL at week 4 the in 48 patients was determined (92.3%), at week 12 in 45 (91.8%) and at week 24 in 42 patients (93.3%). In all patients that the VL was determined its outcome was linked with the treatment continuation or not. CONCLUSIONS: In most patients (80.3%) start and suspension requirements for triple therapy were kept. There is leeway for action and improvement that requires the involvement of all the acting agents.

Clinical experiences with cannabinoids in spasticity management in multiple sclerosis.

INTRODUCTION: Spasticity is a common symptom among patients with multiple sclerosis (MS). This study aims to assess the effectiveness and safety of the combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in clinical practice for the treatment of spasticity in MS. METHODS: Retrospective observational study with patients treated with inhaled THC/CBD between April 2008 and March 2012. Descriptive patient and treatment variables were collected. Therapeutic response was evaluated based on the doctor's analysis and overall impression. RESULTS: Of the 56 patients who started treatment with THC/CBD, 6 were excluded because of missing data. We evaluated 50 patients (42% male) with a median age 47.8 years (25.6-76.8); 38% were diagnosed with primary progressive MS, 44% with secondary progressive MS, and 18% with relapsing-remitting MS. The reason for prescribing the drug was spasticity (44%), pain (10%), or both (46%). Treatment was discontinued in 16 patients because of ineffectiveness (7 patients), withdrawal (4), and adverse effects (5). The median exposure time in patients whose treatment was discontinued was 30 days vs 174 days in those whose treatment continued at the end of the study. THC/CBD was effective in 80% of patients at a median dose of 5 (2-10) inhalations/day. The adverse event profile consisted of dizziness (11 patients), somnolence (6), muscle weakness (7), oral discomfort (2), diarrhoea (3), dry mouth (2), blurred vision (2), agitation (1), nausea (1), and paranoid ideation (1). CONCLUSIONS: THC/CBD appears to be a good alternative to standard treatment as it improves refractory spasticity in MS and has an acceptable toxicity profile.

[Algorithm for diagnosis and treatment of hereditary angioedema as a tool for management]. / Algoritmo de diagnóstico y tratamiento del angioedema hereditario como herramienta para su manejo.

INTRODUCTION: Hereditary angioedema is a disease with low prevalence and high heterogeneity with regards to the severity of the clinical picture, which makes the diagnosis difficult and requires the need for early start of specific treatment in order to prevent complications. OBJECTIVE: To propose a decision algorithm for hereditary angioedema (HAE), based on the evidence available on the diagnosis, clinical assessment, and treatment. The aim is to present the available therapeutic options as well as a decision algorithm to select the most efficient therapy at each time. MATERIAL AND METHODS: Literature search by means of PubMed and other relevant sources. RESULTS: four decision algorithms have been developed for HAE; diagnosis of bradikinin-mediated angioedema, treatment of acute attacks and short and long-term prophylaxis for HAE due to C1 inhibitor deficiency. CONCLUSIONS: The application of a decision algorithm based on the clinical variables helps to select the most efficient therapeutic option at each time and may be a useful tool for the therapeutic approach.

Introducción: El angioedema hereditario es una enfermedad rara de baja prevalencia y gran heterogeneidad en la gravedad del cuadro clínico, lo que dificulta su diagnóstico, y establece la necesidad de iniciar un tratamiento precoz y específico con el fin de evitar complicaciones. Objetivo: Proponer un algoritmo de decisión en el angioedema hereditario (AEH), basado en la evidencia disponible, sobre el diagnóstico, valoración clínica y tratamiento. Se trata de presentar opciones terapéuticas disponibles, así como un algoritmo de decisión para seleccionar el tratamiento más eficiente en cada momento. Material y Métodos: Revisión bibliográfica mediante una búsqueda a través de PubMed y otras fuentes de interés. Resultados: Se han desarrollado cuatro algoritmos de decisión para el AEH; diagnóstico de angioedema mediado por bradicinina, tratamiento del ataque agudo y profilaxis a corto y largo plazo del AEH por déficit del inhibidor C1. Conclusiones: La aplicación de un algoritmo de decisión, en función de unas variables clínicas, ayuda a la selección de la opción terapéutica más eficiente en cada momento y puede ser un instrumento de utilidad en el abordaje terapéutico.

[Improving inpatient pharmacoterapeutic process by Lean Six Sigma methodology]. / Mejora del proceso farmacoterapéutico del paciente hospitalizado mediante la metodología Lean Seis Sigma.

BACKGROUND: Lean Six Sigma methodology has been used to improve care processes, eliminate waste, reduce costs, and increase patient satisfaction. OBJECTIVE: To analyse the results obtained with Lean Six Sigma methodology in the diagnosis and improvement of the inpatient pharmacotherapy process during structural and organisational changes in a tertiary hospital. SCOPE: 1.000 beds tertiary hospital. DESIGN: prospective observational study. The define, measure, analyse, improve and control (DMAIC), were deployed from March to September 2011. An Initial Project Charter was updated as results were obtained. POPULATION AND SAMPLE: 131 patients with treatments prescribed within 24h after admission and with 4 drugs. VARIABLES: safety indicators (medication errors), and efficiency indicators (complaints and time delays). RESULTS: Proportion of patients with a medication error was reduced from 61.0% (25/41 patients) to 55.7% (39/70 patients) in four months. Percentage of errors (regarding the opportunities for error) decreased in the different phases of the process: Prescription: from 5.1% (19/372 opportunities) to 3.3% (19/572 opportunities); Preparation: from 2.7% (14/525 opportunities) to 1.3% (11/847 opportunities); and administration: from 4.9% (16/329 opportunities) to 3.0% (13/433 opportunities). Nursing complaints decreased from 10.0% (2119/21038 patients) to 5.7% (1779/31097 patients). The estimated economic impact was 76,800 euros saved. CONCLUSIONS: An improvement in the pharmacotherapeutic process and a positive economic impact was observed, as well as enhancing patient safety and efficiency of the organization. Standardisation and professional training are future Lean Six Sigma candidate projects.

[Effectiveness and adequacy of tolvaptan prescription in hospitalized patients]. / Efectividad y adecuación de la prescripción de tolvaptán en pacientes hospitalizados.

PURPOSE: To analyse the effectiveness of the use of Tolvaptan and the adequacy of Tolvaptan prescription at a tertiary level hospital. METHODS: Prospective observational study of Tolvaptan prescrip - tion from October of 2010 to December of 2011. RESULTS: 30 patients (60.0% males) were included, 50.0% of which were diagnosed with heart failure and 30.0% with SIADH. Tolvaptan allowed achieving sodium levels higher than 135 mEq/L in 53.3% of the patients with a mean baseline value of 125.3±7.3 mEq/L. The median treatment duration was 5.0 days (interquartile range=3-45). A significant increase of uric acid associated to Tolvaptan treatment was observed. The prescription was in agreement to what has been established in GFT in 63.3% of the cases. CONCLUSIONS: Tolvaptan increases sodium levels by 7.5 mEq/L, both in SIADH-associated hyponatremia and in heart failure, with an appropriate safety profile.

Objetivo: Analizar la efectividad del uso de tolvaptán y la adecuación de su prescripción en un hospital de tercer nivel. Método: Estudio observacional prospectivo de las prescripciones de tolvaptán desde octubre de 2010 hasta diciembre de 2011. Resultados: Se incluyeron 30 pacientes (60,0% varones), 50,0% diagnosticados de insuficiencia cardíaca y 30,0% de SIADH. Tolvaptán permitió alcanzar niveles de sodio superiores a 135 mEq/L en el 53,3% de los pacientes que partían con una media de 125,3±7,3 mEq/L. La mediana de días de tratamiento fue de 5,0 (rango intercuartílico = 3-45). Se observó un incremento significativo de los niveles de ácido úrico asociado al tratamiento con tolvaptán. La prescripción se adecuó a lo establecido en la GFT en el 63,3% de los casos. Conclusiones: Tolvaptán incrementa un 7,5 mEq/L los niveles de sodio tanto en hiponatremia secundaria al SIADH como en insuficiencia cardiaca.

[Evaluation of the written informed consent form in clinical trials]. / Evaluación de la hoja de información al paciente y del consentimiento informado en ensayos clínicos.

PURPOSE: To assess the quality of the written informed consent form (WICF) in clinical trials. MATERIAL AND METHODS: Retrospective observational study was performed on 50 WICF of clinical trials started between 2010 and 2011. The quality of the content of the WICF was assessed using the "Guideline for Good Clinical Practice" contained in the CPMP/ICH/135/95 of the European Medicines Agency. Legibility indexes were applied to the WICF. RESULTS: The WICF was correct in all aspects in 10% of the clinical trial; five sections were correct in all WICF: "trial involves research", "trials goals", "participation is voluntary and the subject may withdraw at any time without penalty", "study personnel with access to medical records" and "documents that identify the patient are confidential". Aspects less present were "the subject's responsibilities" and "available alternatives". All WICF required clarification by the Ethics Committee (EC), with a mean of 4.24 (SD=1.87) changes per WICF. The WICF showed good results in the indices of readability. Almost all (98%) of WICF were considered with an acceptable readability. CONCLUSIONS: Compliance with different aspects that must appear in the WICF is high. Aspects to improve are the subject's responsibilities and available alternatives to the clinical trial. The complexity of reading the WICF is suitable for the average population. The review of the WICF by the EC guarantees the access to comprehensive and appropriate information.

Pharmacogenetic study of ABCB1 and CYP3A5 genes during the first year following heart transplantation regarding tacrolimus or cyclosporine levels.

Pharmacogenetics explains part of the interindividual variability in drug responses. Many published works about the effects of single nucleotide polymorphisms (SNPs) on immunosuppressive drug blood levels present contradictory results. We evaluated the SNPs in ABCB1 (glycoprotein P) and CYP3A5 (metabolic enzyme) genes, seeking correlate them with tacrolimus or cyclosporine levels during the first year after heart transplantation. One blood sample was obtained from each of 41 patients: 26 treated with cyclosporine and 15 with tacrolimus. We characterize the SNPs rs1045642, 1128503, 2032582, 2235013, 2235033, 2229109, 3213619, 9282564 in ABCB1 and rs10264272, 776746 in CYP3A5 genes using the Sequenom platform. The genotype was correlated with the trough drug blood levels corrected by dose and body weight (C(0)/(dose/weight)). The CYP3A5 SNPs showed the expected behavior, where patients carrying the low expression variants displayed higher drug blood levels of more than 100% of the normal expression variant level even at 1 year posttransplantation. To correlate ABCB1 SNPs, the variants described to cause higher blood levels in rs1045642, 1128503, 2032582 (in linkage disequilibrium) showed this effect only until 4 months posttransplantation among patients treated with cyclosporine (more than 100% higher than the other variant). After 1 year, concentrations reached a stable phase with normal levels. The observation was not so evident among those treated with tacrolimus. Remarkably, at this point, patients treated with cyclosporine, showed a significant (P < .01) difference between the two variants of rs9282564 and even if it was not significant there was also a tendency among the intronic rs2235013 and 2235033. The results indicated that SNPs in ABCB1 gene seem to not be relevant for long-term dose adjustment in patients, but to show an effect during the first 4 months.