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OBJECTIVES: To characterize amikacin population pharmacokinetics in patients with hypoalbuminaemia and to develop a model-based interactive application for amikacin initial dosage. METHODS: A population pharmacokinetic model was developed using a non-linear mixed-effects modelling approach (NONMEM) with amikacin concentration-time data collected from clinical practice (75% hypoalbuminaemic patients). Goodness-of-fit plots, minimum objective function value, prediction-corrected visual predictive check, bootstrapping, precision and bias of parameter estimates were used for model evaluation. An interactive model-based simulation tool was developed in R (Shiny and R Markdown). Cmax/MIC ratio, time above MIC and AUC/MIC were used for optimizing amikacin initial dose recommendation. Probabilities of reaching targets were calculated for the dosage proposed. RESULTS: A one-compartment model with first-order linear elimination best described the 873 amikacin plasma concentrations available from 294 subjects (model development and external validation groups). Estimated amikacin population pharmacokinetic parameters were CL (L/h) = 0.525â+â4.78 × (CKD-EPI/98) × (0.77 × vancomycin) and V (L) = 26.3 × (albumin/2.9)-0.51 × [1â+â0.006 × (weight - 70)], where CKD-EPI is calculated with the Chronic Kidney Disease Epidemiology Collaboration equation. AMKdose is a useful interactive model-based application for a priori optimization of amikacin dosage, using individual patient and microbiological information together with predefined pharmacokinetic/pharmacodynamic (PKPD) targets. CONCLUSIONS: Serum albumin, total bodyweight, estimated glomerular filtration rate (using the CKD-EPI equation) and co-medication with vancomycin showed a significant impact on amikacin pharmacokinetics. A powerful interactive initial dose-finding tool has been developed and is freely available online. AMKdose could be useful for guiding initial amikacin dose selection before any individual pharmacokinetic information is available.
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Amicacina , Hipoalbuminemia , Antibacterianos , Taxa de Filtração Glomerular , Humanos , Modelos Biológicos , VancomicinaRESUMO
AIMS: Therapeutic drug monitoring (TDM) of trough serum infliximab concentrations has been mainly used in case of loss of response in patients with inflammatory bowel disease (IBD). The aim of this study was to evaluate the effectiveness and safety of a multidisciplinary early proactive TDM (mep-TDM) programme for dose adjustment. METHODS: A 3-year prospective study was conducted based on a sample of 81 patients who started treatment and were subsequently subjected to mep-TDM with the first control at week 14. Data of a historical control group of 72 patients treated with infliximab and managed with empirical dosing were included. Effectiveness variables were treatment failure, IBD-related surgery and IBD-related hospitalization. Safety variables were serious infusion reactions (SIRs) and adverse reactions. Cox regression was used for survival analysis. RESULTS: In the mep-TDM study group, compared to the control group, there was a significant reduction in the risk of treatment failure (hazard ratio [HR]: 0.51; 95% confidence interval [CI]: 0.27-0.92; P = .037), IBD-related surgery (HR: 0.14; 95% CI: 0.03-0.65; P = .012) and hospitalization (HR: 0.38; 95% CI: 0.17-0.87; P = .022). SIRs were lower in the mep-TDM group (2.5% vs 10.4%; P < .050); the incidence of adverse reactions was similar (3.7% vs 3.9%; p > .999). CONCLUSION: This study found that compared to empirical dosing, mep-TDM is associated with improved efficacy and safety of infliximab therapy, reduced IBD-related hospitalization and surgery and incidence of SIRs, and increasing long-term durability of treatment effects.
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Monitoramento de Medicamentos , Doenças Inflamatórias Intestinais , Fármacos Gastrointestinais/efeitos adversos , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/efeitos adversos , Estudos ProspectivosRESUMO
The medication in an electronic prescribing system (EPS) does not always match the patient's actual medication. This prospective study analyzes the discrepancies (any inconsistency) between medication prescribed using an EPS and the medication revised by the clinical pharmacist upon admission to the observation area of the emergency department (ED). Adult patients with multimorbidity and/or polypharmacy were included. The pharmacist used multiple sources to obtain the revised medication list, including patient/carer interviews. A total of 1654 discrepancies were identified among 1131 patients. Of these patients, 64.5% had ≥1 discrepancy. The most common types of discrepancy were differences in posology (43.6%), commission (34.7%), and omission (20.9%). Analgesics (11.1%), psycholeptics (10.0%), and diuretics (8.9%) were the most affected. Furthermore, 52.5% of discrepancies affected medication that was high-alert for patients with chronic illnesses and 42.0% of medication involved withdrawal syndromes. Discrepancies increased with the number of drugs (ρ = 0.44, p < 0.01) and there was a difference between non-polypharmacy patients, polypharmacy ones and those with extreme polypharmacy (p < 0.01). Those aged over 75 years had a higher number of prescribed medications and discrepancies occurred more frequently compared with younger patients. The number of discrepancies was larger in women than in men. The EPS medication record requires verification from additional sources, including patient and/or carer interviews.
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Patients with enteral access usually receive oral drugs via feeding tubes and correct drug administration remains a challenge. The aim of this study was to identify common medication delivery errors (MDEs) in outpatients with percutaneous endoscopic gastrostomy (PEG) and evaluate their association with the need for tube replacement due to deterioration or clogging. A 2-year retrospective study that comprised adult outpatients with a placed/replaced PEG tube and whose electronic medical record included home medication was carried out. Treatment with medication that should not be crushed and administered through an enteral feeding tube was considered an MDE. We included 269 patients and 213 MDEs (20% of oral prescriptions) were detected in 159. Ninety-two percent of the medications associated with MDEs could be substituted by appropriate formulations. Tube replacement due to obstruction was needed in 85 patients. MDEs were associated with increased risk for tube replacement (OR 2.17; 95% CI 1.10-4.27). Omeprazole enteric-coated capsules were associated with the greatest risk (OR 2.24; 95% CI 1.01-4.93). PEG outpatients are highly exposed to MDEs, leading to a significant increase in the odds of tube replacement, mainly when treated with omeprazole. The use of appropriate alternative therapies would prevent unnecessary adverse events.
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Nutrição Enteral , Gastrostomia , Adulto , Humanos , Nutrição Enteral/efeitos adversos , Gastrostomia/efeitos adversos , Pacientes Ambulatoriais , Estudos Retrospectivos , OmeprazolRESUMO
Each year, infections caused around the 25% of neonatal deaths. Early empirical treatments help to reduce this mortality, although optimized dosing regimens are still lacking. The aims were to develop and validate a gentamicin physiologically-based pharmacokinetic (PBPK) model and then potentially explore dosing regimens in neonates using pharmacokinetic and pharmacodynamic criteria. The PBPK model developed consisted of 2 flow-limited tissues: kidney and other tissues. It has been implemented on a new tool called PhysPK, which allows structure reusability and evolution as predictive engine in Model-Informed Precision Dosing (MIPD). Retrospective pharmacokinetic information based on serum levels data from 47 neonates with gestational age between 32 and 39 weeks and younger than one-week postnatal age were used for model validation. The minimal PBPK model developed adequately described the gentamicin serum concentration-time profile with an average fold error nearly 1. Extended interval gentamicin dosing regimens (6 mg/kg q36h and 6 mg/kg q48h for term and preterm neonates, respectively) showed efficacy higher than 99% with toxicity lower than 10% through Monte Carlo simulation evaluations. The gentamicin minimal PBPK model developed in PhysPK from literature information, and validated in preterm and term neonates, presents adequate predictive performance and could be useful for MIPD strategies in neonates.
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Objective: To evaluate the predictive performance of eight renal function equations to describe amikacin elimination in a large standard population with a wide range of age. Methods: Retrospective study of adult hospitalized patients treated with amikacin and monitored in the clinical pharmacokinetics laboratory of a pharmacy service. Renal function was calculated as Cockcroft-Gault with total, adjusted and ideal body weight, MDRD-4, CKD-EPI, rLM, BIS1, and FAS. One compartment model with first-order elimination, including interindividual variability on clearance and volume of distribution and combined residual error model was selected as a base structural model. A pharmaco-statistical analysis was performed following a non-linear mixed effects modeling approach (NONMEM 7.3 software). Results: 198 patients (61 years [18-93]) and 566 measured amikacin plasma concentrations were included. All the estimated glomerular filtration rate and creatinine clearance equations evaluated described properly the data. The linear relationship between clearance and glomerular filtration rate based on rLM showed a statistically significant improvement in the fit of the data. rLM must be evaluated carefully in renal failure for amikacin dose adjustment. Conclusions: Revised Lund-Malmö (rLM) and CKD-EPI showed the superior predictive performance of amikacin drug elimination comparing to all the alternative metrics evaluated.
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Amicacina/administração & dosagem , Antibacterianos/administração & dosagem , Nefropatias/complicações , Modelos Biológicos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Amicacina/farmacocinética , Antibacterianos/farmacocinética , Creatinina/metabolismo , Relação Dose-Resposta a Droga , Feminino , Taxa de Filtração Glomerular , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Dinâmica não Linear , Estudos Retrospectivos , Distribuição Tecidual , Adulto JovemRESUMO
BACKGROUND: The objective of this study was to characterize the pharmacokinetics (PK) of digoxin in pregnant women and its potential implications for drug dosing. METHODS: Serum digoxin concentrations (SDCs) obtained in pregnant women treated for fetal supraventricular tachycardia (SVT) was retrospectively collected. PK analysis was comparatively performed using a two-stage approach (PKS™) and a Population PK approach (NONMEM™). As clinical outcome the fetal heart rate was recorded. RESULTS: A total of 42 SDCs were obtained from 8 women in the 3rd trimester of pregnancy (mean age 33.0 years). The PK parameters estimated by both two-stage (volume of distribution (Vd) = 682.0 L, CV = 47.5%; serum clearance (CL) = 16.1 L/h, CV = 19%) and population approaches (Vd = 731.3 L, CV = 30.5%; CL = 18.7 L/h, CV = 17.8%) are very similar and show a clear trend of increasing drug disposition in the third trimester of pregnancy. An oral loading dose of 0.5 mg/8 h during 24 h followed by a maintenance regimen of 0.5 mg/12 h been recommended to start treatment. CONCLUSIONS: Despite the small population, these parameters could be used as a guide to calculate the initial dosage requirements in the third trimester of pregnancy for treating fetal SVT. In addition, maternal SDCs should be routinely monitored for dosage adjustment purposes.
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Antiarrítmicos/administração & dosagem , Digoxina/administração & dosagem , Doenças Fetais/tratamento farmacológico , Taquicardia Supraventricular/tratamento farmacológico , Adulto , Antiarrítmicos/farmacocinética , Digoxina/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Doenças Fetais/fisiopatologia , Humanos , Modelos Biológicos , Dinâmica não Linear , Gravidez , Terceiro Trimestre da Gravidez , Estudos Retrospectivos , Distribuição Tecidual , Adulto JovemRESUMO
A clinical nutrition support pharmacist training program, in collaboration with the Spanish Foundation of Hospital Pharmacy, Spanish Society of Clinical Nutrition, Abbott Nutrition International, University of Tennessee, College of Pharmacy and Regional One Health, is described. Nutrition support pharmacists from Spain were selected to participate in a one-month training program with an experienced board-certified nutrition support pharmacist faculty member within an interdisciplinary nutrition support team environment in the U.S. Participants were expected to actively engage in an advanced clinical practice role with supervision. Clinical activities included daily intensive patient monitoring, physical assessment, critical evaluation of the patient and development of an appropriate treatment plan for patients receiving either enteral or parenteral nutrition therapy. Upon successful completion of the training program, participants were anticipated to incorporate these techniques into their current practice in Spain and to train other pharmacists to function in an advanced clinical role independently or within an interdisciplinary nutrition support team environment.
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OBJECTIVE: Dual PEGylated interferon-α (PEG-IFN) and ribavirin therapy has been the main hepatitis C virus (HCV) treatment of the last decade. Current direct-acting antiviral agents have improved the outcome of therapy but also have increased the cost and management complexity of treatment. The current study analyzes host genetics, viral and clinical predictors of sustained viral response (SVR) to dual PEG-IFN and ribavirin therapy in a representative Spanish population. METHODS: Observational prospective multicentre pharmacogenetic cohort study conducted in 12 different hospitals of 12 different Spanish regions. A total of 98 patients with SVR and 106 with non-SVR in response to PEG-IFN and ribavirin therapy were included. 33 single nucleotide polymorphisms located in 24 different genes related with inflammatory, immune and virus response were selected. Clinical and viral data were also analyzed as candidate of SVR predictors. RESULTS: IL-28B (rs12979860, rs7248668, rs8105790, rs8099917) and TNFRSF1B (rs1061622) genotypes, as well as TNFRSF1B/IL-10/TNFα (-308) non-TTG and TNFRSF1B/IL- 10/IL-4 non-TTC haplotypes together with lower age, lower basal HCV RNA load, higher basal serum LDL cholesterol values, VHC genotypes 2 and 3 and basal low grade fibrosis 0-2 were associated with a SVR in the univariate analysis. Independent predictors of SVR in the multivariate analysis were IL-28B rs12979860 CC, TNFRSF1B/IL-10/IL-4 non-TTC along with low baseline HCV RNA load and HCV genotypes 2 and 3. CONCLUSIONS: IL-28B rs12979860 CC, TNFRSF1B/ IL-10/ IL-4 non-TTC haplotype, low baseline HCV RNA load and HCV genotypes 2 and 3 may help to predict successful outcome to PEG-IFN/ribavirin therapy in Spanish population.
Objetivo: El interferon-ï¡ï pegilado (IFN-PEG) junto a ribavirina ha sido el principal tratamiento de la infeccion por el virus de la hepatitis C (VHC) de la ultima decada. Los agentes antivirales de accion directa actuales han mejorado los resultados de la terapia, pero tambien han aumentado el costo y la gestion de la complejidad del tratamiento. El presente estudio analiza factores geneticos de los pacientes, asi como predictores virales y clinicos de respuesta sostenida viral (RSV) al tratamiento con IFN-PEG y ribavirina en poblacion Espanola. Métodos: Estudio farmacogenetico, multicentrico, prospectivo, observacional de cohortes realizado en 12 hospitales diferentes de 12 comunidades autonomas diferentes. Se incluyeron un total de 98 pacientes con RVS y 106 sin SVR al tratamiento con IFNPEG y ribavirina. Se seleccionaron 33 polimorfismos de nucleotido unico ubicados en 24 genes diferentes relacionados con la respuesta inflamatoria, inmunologica y viral. Los datos clinicos y virales tambien se analizaron como candidatos predictores de RVS. Resultados: Los genotipos IL-28B (rs12979860, rs7248668, rs8105790, rs8099917) y TNFRSF1B (rs1061622), asi como los haplotipos TNFRSF1B / IL-10 / TNFï¡ï (-308) no-TTG y TNFRSF1B / IL-10 / IL-4 no-TTC junto con la menor edad, menor carga de ARN-VHC basal, valores elevados de colesterol LDL en suero basal, genotipos VHC2 y 3 y bajo grado de fibrosis basal (0-2) se asociaron con una RVS en el analisis univariante. Los predictores independientes de RVS en el analisis multivariante fueron el genotipo IL-28B rs12979860 CC, el haplotipo TNFRSF1B / IL-10 / IL-4 no-TTC junto con los bajos niveles basales de VHCARN y los genotipos virales VHC2 y 3. Conclusiones: El genotipo IL-28B rs12979860 CC, el haplotipo TNFRSF1B / IL-10 / IL-4 haplotipos no-TTC, la carga viral basal baja y los genotipos del VHC2 y 3 pueden ayudar a predecir una buena respuesta a la terapia con IFN-PEG y ribavirina en poblacion espanola.
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Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Interferon-alfa/uso terapêutico , Ribavirina/uso terapêutico , Adulto , Estudos de Coortes , Feminino , Hepacivirus , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Polietilenoglicóis , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Espanha , Carga ViralRESUMO
OBJECTIVES: Evaluation of the performance of a modified Enzyme Multiplied Immunoassay Technique for therapeutic drug monitoring of plasma free mycophenolic acid (fMPA) concentrations. DESIGN AND METHODS: A fMPA assay was developed on a Viva-E analyzer. A study of prior ultrafiltration conditions and analytical validation of the EMIT assay were performed. RESULTS: The method was reliable and reproducible. CONCLUSIONS: fMPA levels can be monitored using this EMIT assay with the advantage of being an automated method.