Clopidogrel-induced thrombotic microangiopathy: a case report.

Thrombotic microangiopathy is a serious condition that can be precipitated by exposure to certain medications. Although rare, it is life threatening and requires a high index of clinical suspicion, appropriate laboratory testing and immediate cessation of the offending agent. We present a case of a 75-year-old man with a history of ischaemic heart disease treated with clopidogrel and aspirin. One month after initiating the treatment he developed microangiopathic haemolytic anaemia and thrombocytopenia. Extensive clinical and laboratory investigations suggested thrombotic microangiopathy secondary to clopidogrel. The drug was immediately discontinued and treatment with intravenous corticosteroids was started. Within a week the patient's laboratory parameters normalised, indicating successful recovery. This case highlights the role of early detection and immediate discontinuation of suspected medication in the effective management of clopidogrel-induced thrombotic microangiopathy. Healthcare professionals should consider drug-induced thrombotic microangiopathy as a possible diagnosis in patients receiving clopidogrel who present with thrombocytopenia and microangiopathic haemolytic anaemia.

Factor B Inhibition with Iptacopan in Recurrent C3 Glomerulopathy Following Kidney Transplant: A Report of Two Cases.

C3 glomerulopathy is a rare disease caused by fluid phase dysregulation of the alternative complement pathway. Currently, treatment depends on clinical and histological severity and includes nephroprotection, unspecific immunosuppression, and terminal complement blockers (C5), without having an etiological treatment approved. C3 glomerulopathy has high recurrence rates after kidney transplantation with a high risk of graft loss. Fortunately, new molecules are being developed that specifically target the proximal alternative complement pathway, such as iptacopan, a factor B inhibitor that showed promising results in native kidneys and cases of transplant recurrence in a phase 2 clinical trial. We present 2 "real-world" cases of C3 glomerulopathy recurrence in kidney allografts treated with iptacopan, with initial excellent clinical response and safety profile, especially with early introduction. We also present follow-up biopsies that showed no C3 deposition during factor B inhibition. Our cases suggest that proximal blockade of the alternative complement pathway can be effective and safe in the treatment of C3 glomerulopathy recurrence in kidney transplantation, bringing other questions such as dual blockade (eg, in C3 and C5), the optimal patient profile to benefit from factor B inhibition or treatment duration and its potential use in other forms of membranoproliferative glomerulonephritis (eg, immune complex-mediated).

Tocilizumab Dose Tapering Based on a Model-Based Algorithm is Feasible in Clinical Practice: A Short Communication.

BACKGROUND: Tocilizumab in the treatment of rheumatoid arthritis (RA) is a potential candidate for concentration-guided tapering because the standard dose of tocilizumab results in a wide range of serum concentrations, usually above the presumed therapeutic window, and an exposure-response relationship has been described. However, no clinical trials have been published to date on this subject. Therefore, the objective of this study was to assess the feasibility of the tapering of intravenous (iv) tocilizumab with the use of a pharmacokinetic model-based algorithm in RA patients. METHODS: A randomized controlled trial with a double-blind design and follow-up of 24 weeks was conducted. RA patients who received the standard of tocilizumab for at least the past 24 weeks, which is 8 mg/kg every 4 weeks, were included. Patients with a tocilizumab serum concentration above 5 mg/L at trough were randomized between concentration-guided dose tapering, referred to as therapeutic drug monitoring (TDM), or the standard 8 mg/kg dose. In the TDM group, the tocilizumab dose was tapered with a recently published model-based algorithm to achieve a target concentration of 4-6 mg/L after 20 weeks of dose tapering. RESULTS: Twelve RA patients were included and 10 were randomized between the TDM and standard dose group. The study was feasible regarding the predefined feasibility criteria and patients had a positive attitude toward therapeutic drug monitoring. In the TDM group, the tocilizumab trough concentration within patients decreased on average by 24.5 ± 18.3 mg/L compared with a decrease of 2.8 ± 12 mg/L in the standard dose group. None of the patients in the TDM group reached the drug range of 4-6 mg/L. Instead, tocilizumab concentrations of 1.6 and 1.5 mg/L were found for the 2 patients who completed follow-up on the tapered dose. No differences in RA disease activity were observed between the 2 study groups. CONCLUSIONS: This study was the first to show that it is feasible to apply a dose-reduction algorithm based on a pharmacokinetic model in clinical practice. However, the current algorithm needs to be optimized before it can be applied on a larger scale.

Predictive performance of glomerular filtration rate equations based on cystatin C, creatinine and their combination in critically ill patients.

OBJECTIVE: 24-hour urine creatinine clearance (ClCr 24 hours) remains the gold standard for estimating glomerular filtration rate (GFR) in critically ill patients; however, simpler methods are commonly used in clinical practice. Serum creatinine (SCr) is the most frequently used biomarker to estimate GFR; and cystatin C, another biomarker, has been shown to reflect GFR changes earlier than SCr. We assess the performance of equations based on SCr, cystatin C and their combination (SCr-Cyst C) for estimating GFR in critically ill patients. METHODS: Observational unicentric study in a tertiary care hospital. Patients with cystatin C, SCr and ClCr 24 hours measurements in ±2 days admitted to an intensive care unit were included. ClCr 24 hours was considered the reference method. GFR was estimated using SCr-based equations: Chronic Kidney Disease Epidemiology Collaboration based on creatinine (CKD-EPI-Cr) and Cockcroft-Gault (CG); cystatin C-based equations: CKD-EPI-CystC and CAPA; and Cr-CystC-based equations: CKD-EPI-Cr-CystC. Performance of each equation was assessed by calculating bias and precision, and Bland-Altman plots were built. Further analysis was performed with stratified data into CrCl 24 hours <60, 60-130 and ≥130 mL/min/1.73 m2. RESULTS: We included 275 measurements, corresponding to 186 patients. In the overall population, the CKD-EPI-Cr equation showed the lowest bias (2.6) and best precision (33.1). In patients with CrCl 24 hours <60 mL/min/1.73 m2, cystatin-C-based equations showed the lowest bias (<3.0) and CKD-EPI-Cr-CystC was the most accurate (13.6). In the subgroup of 60≤ CrCl 24 hours <130mL/min/1.73 m2, CKD-EPI-Cr-CystC was the most precise (20.9). However, in patients with CrCl 24 hours ≥130mL/min/1.73 m2, cystatin C-based equations underestimated GFR, while CG overestimated it (22.7). CONCLUSIONS: Our study showed no evidence of superiority of any equation over the others for all evaluated parameters: bias, precision and Lin's concordance correlation coefficient. Cystatin C-based equations were less biased in individuals with impaired renal function (GFR <60 mL/min/1.73 m2). CKD-EPI-Cr-CystC performed properly in patients with GFR from 60-130 mL/min/1.73 m2 and none of them were accurate enough in patients ≥130 mL/min/1.73 m2.

Creatine Kinase Elevation in Autosomal Dominant Polycystic Kidney Disease Patients on Tolvaptan Treatment.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cause of end-stage kidney disease. Currently, tolvaptan is the only treatment that has proven to delay disease progression. The most notable side effect of this therapy is drug-induced liver injury; however, recently, there have been two reports of creatine kinase (CK) elevation in ADPKD patients on tolvaptan treatment. We set out to monitor and determine the actual incidence of CK elevation and evaluate its potential association with other clinical factors. METHODS: This is an observational retrospective multicenter study performed in rapidly progressive ADPKD patients on tolvaptan treatment from Barcelona, Spain. Laboratory tests, demographics, treatment dose, and reported symptoms were collected from October 2018 to March 2021. RESULTS: Ninety-five patients initiated tolvaptan treatment during follow-up. The medication had to be discontinued in 31 (32.6%) patients, primarily due to aquaretic effects (12.6%), elevated liver enzymes (8.4%), and symptomatic or persistently elevated CK levels (3.2%). Moreover, a total of 27 (28.4%) patients had elevated CK levels, with most of them being either transient (12.6%), mild and asymptomatic (4.2%), or resolved after dose reduction (3.2%) or temporary discontinuation (2.1%). CONCLUSION: We pre-sent the largest cohort that has monitored CK levels in a real-life setting, finding them elevated in 28.4% of patients. More research and monitoring will help us understand the clinical implications and the pathophysiological mechanism of CK elevation in this population.

Tigecycline population pharmacokinetics in critically ill patients with decompensated cirrhosis and severe infections.

OBJECTIVES: Physiopathological changes in advanced cirrhosis could alter tigecycline pharmacokinetics (PK), thus affecting serum drug concentrations and compromising target attainment. We aimed to describe tigecycline PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target. METHODS: Serum concentrations and covariates were obtained from patients with severe infections under tigecycline treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate tigecycline exposure to assess the PTA. RESULTS: Twenty critically ill patients were enrolled in the study. Data were best described by a two-compartment linear model. Mean ± SD parameter estimates for clearance (CL), intercompartmental clearance (Q), central and peripheral volumes of distribution (V1 and V2) were 14.8 ± 11 L/h, 38.4 ± 24 L/h, 63.7 ± 14 L and 233 ± 30 L, respectively. MELD score significantly influenced tigecycline CL, and total serum proteins significantly affected V1. Monte Carlo simulations showed that tigecycline elimination is hampered as MELD score values increase, consequently requiring lower drug doses. Patients with hypoproteinaemia would have lower peak tigecycline concentrations but similar steady-state concentrations compared with patients with normoproteinaemia. CONCLUSIONS: Our study confirms that tigecycline dose adjustment is needed in severe hepatic dysfunction and suggests using the MELD score for dose optimization since it is identified as a covariate that significantly influences tigecycline CL. Dosing regimens are recommended to reach several PK/PD targets considering this clinical variable and any MIC within the susceptibility range.

Evaluación de las concentraciones plasmáticas de voriconazol en práctica clínica / Assessment of plasma voriconazole concentrations in clinical practice

Introducción: Voriconazol presenta una alta variabilidad interindividual en sus concentraciones plasmáticas (Cp). Los objetivos son: (i) describir sus Cp en una cohorte adulta, (ii) estudiar sus potenciales causas de variabilidad y (iii) relacionarlas con las recomendaciones de monitorización farmacocinética actuales. Método: Estudio observacional retrospectivo, incluyendo pacientes con ≥1 determinación de Cp mínima (Cmin) de voriconazol durante 2017. Resultados: Se analizaron 165 Cmin correspondientes a 51 pacientes. La mediana de Cmin fue de 2,4µg/mL (IQR:1,4-3,6), siendo <1µg/mL en 26 casos y >4µg/mL en 34. Se observaron Cmin significativamente superiores en >65 años (p=0,006) y en pacientes con albúmina <27g/L (p<0,001). Siguiendo las recomendaciones de monitorización de las Cp de voriconazol según la guía ESCMID-ECMM-ERS, se detectarían el 91,1% de Cmin que resultaron fuera de intervalo. Conclusiones: Observamos un 36,4% de las Cmin de voriconazol fuera del intervalo óptimo. Identificamos la edad y la concentración de albúmina como factores que influencian las Cp. (AU)

Introduction: Voriconazole presents a high interindividual variability in plasma concentrations. We aimed to: (i) describe plasma voriconazole concentrations (PVC) of an adult cohort, (ii) identify potential causes of variability and (iii) relate them with current pharmacokinetic monitoring recommendations. Method: Observational retrospective study. All patients with at least one determination of PVC during 2017 were included. Results: A total of 165 trough concentrations (Ctrough) were analyzed from 51 patients. The median Ctrough was 2.4μg/mL (IQR:1.4-3.6). Ctrough were <1μg/mL in 26 cases and >4 μg/mL in 34. Significantly higher concentrations were ob-served in patients older than 65 years (p=0.006) and in patients with albumin levels <27g/L (p<0.001). Following PVC’s monitoring recommendation from ESCMID-ECMM-ERS’s guideline, we would detect the 91.1% of Ctrough out of the interval. Conclusions: We observed 36.4% of PVC outside of its optimal range. We identified age and albumin concentration as factors that influence PVC (AU)

Once-daily 1 g ceftriaxone optimizes exposure in patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration.

PURPOSE: Ceftriaxone total and unbound pharmacokinetics (PK) can be altered in critically ill patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration (CVVHDF). The objective of this study was to determine the dosing strategy of ceftriaxone that maximizes the probability of maintaining the concentration above the MIC of the susceptible bacteria (≤2 mg/L by the EUCAST) for a 100% of the dosing interval (100% ƒuT>MIC). METHODS: In a prospective PK study in the intensive care units of two tertiary Spanish hospitals, six timed blood samples were collected per patient; for each sample, ceftriaxone total and unbound concentrations were measured using a liquid chromatography coupled to tandem mass spectrometry method. Population PK analysis and Monte-Carlo simulations were performed using NONMEMv.7.3®. RESULTS: We enrolled 8 critically ill patients that met the inclusion criteria (47 blood samples). Median age (range) was 70 years (47-85), weight 72.5 kg (40-95), albumin concentration 24.2 g/L (22-34), APACHE II score at admission 26 (17-36), and SOFA score on the day of study 12 (9-15). The unbound fraction (ƒu) of ceftriaxone was 44%, and total CL was 1.27 L/h, 25-30% higher than the CL reported in septic critically ill patients not receiving renal replacement therapies, and dependent on albumin concentration and weight. Despite this increment in ƒu and CL, Monte-Carlo simulations showed that a dose of 1 g once-daily ceftriaxone is sufficient to achieve a 100% ƒuT>MIC for MICs ≤2 mg/L for any range of weight and albumin concentration. CONCLUSION: Once-daily 1 g ceftriaxone provides optimal exposure in critically ill patients with septic shock and hypoalbuminemia receiving CVVHDF.

Meropenem population pharmacokinetics in patients with decompensated cirrhosis and severe infections.

OBJECTIVES: Meropenem pharmacokinetics (PK) may be altered in patients with cirrhosis, hampering target attainment. We aimed to describe meropenem PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target. METHODS: Serum concentrations and covariates were obtained from patients with severe infections under meropenem treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate meropenem exposure to assess the PTA. RESULTS: Fifty-four patients were enrolled in the study. Data were best described by a one-compartment linear model. The estimated typical mean value for clearance (CL) was 8.35 L/h and the estimated volume of distribution (V) was 28.2 L. Creatinine clearance (CLCR) and MELD score significantly influenced meropenem CL, and acute-on-chronic liver failure (ACLF) significantly affected V. Monte Carlo simulations showed that a lower meropenem dose would be needed as CLCR decreases and as the MELD score increases. Patients with ACLF would have lower peak meropenem concentrations but similar steady-state concentrations compared with patients with no ACLF. CONCLUSIONS: Our study identified two new covariates that influence meropenem PK in patients with decompensated cirrhosis in addition to CLCR: MELD score and ACLF. Dosing regimens are recommended to reach several PK/PD targets considering these clinical variables and any MIC within the susceptibility range.

Evaluation of dose-tapering strategies for intravenous tocilizumab in rheumatoid arthritis patients using model-based pharmacokinetic/pharmacodynamic simulations.

PURPOSE: Tocilizumab is a humanized monoclonal antibody approved for rheumatoid arthritis treatment. In clinical practice, empirical dose-tapering strategies are implemented in patients showing sustained remission or low disease activity (LDA) to avoid overtreatment and reduce costs. Since rational adaptive-dosing algorithms taking the full pharmacokinetic (PK)/pharmacodynamic (PD) characteristics into account are currently lacking, we aimed to develop novel tapering strategies and compare them with currently used empirical ones. METHODS: Four strategies were simulated on a virtual population. In all of them, the same initial dose was administered every 28 days for six consecutive months. Then, different strategies were considered: (1) label-dosing; (2) mild empirical dose-tapering; (3) intense empirical dose-tapering; (4) therapeutic drug monitoring (TDM)-guided dose-tapering. The different strategies were evaluated on the proportion of patients who maintain remission/LDA 1 year after the intervention. Cost-savings of direct drug costs were also estimated as relative dose intensity. RESULTS: The overall proportion of simulated patients in remission/LDA after 1 year of the intervention was comparable between the mild empirical and the TDM-guided dose-tapering strategies, and much lower for the intense empirical dose-tapering strategy (80.3%, 78.2%, and 69.0%, respectively). Likewise, 1-year flare rates were lower for the mild empirical and TDM-guided tapering strategies. The relative dose intensity was lowest for the intense empirical dose-tapering, followed by the TDM-guided and the mild empirical dose-tapering approaches (61.2%, 71.0%, and 80.4%, respectively). CONCLUSION: We demonstrated that the TDM-guided strategy using model-based algorithms performed similarly to mild empirical dose-tapering strategies in overall remission/LDA rates but is superior in cost-savings.

The safety of antimicrobials for the treatment of community-acquired pneumonia.

Introduction: Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide, and its prevalence continues to increase. Despite the efficacy of antimicrobials, their safety and tolerability remain topics of interest and concern for clinicians and patients alike.Areas covered: This review outlines the main antimicrobial classes recommended for the empirical treatment of CAP in current guidelines, together with a potential new class. Each pharmacological group underwent a safety evaluation based on all available data about drug-related toxicities. The authors also present their mechanisms of action, their pharmacokinetic and pharmacodynamic properties, and the main clinical studies.Expert opinion: Overall, antimicrobials currently marketed for the treatment of CAP are well tolerated and generally safe. However, unusual and sometimes serious adverse effects can occur in susceptible populations. Attention should be paid to identifying patients at risk of developing drug-related toxicities because, although most effects are transient, some could be disabling, permanent, or even fatal. Post-marketing surveillance remains crucial for gathering data to overcome the limitations of preclinical and clinical studies in estimating the true prevalence of drug-related adverse events.

Administración intrapleural secuencial de agentes fibrinolíticos y dornasa alfa en el empiema. Protocolo de uso clínico en base a su estabilidad fisicoquímica / Sequential intrapleural administration of fibrinolytic drugs and dornase alfa for empyema management. Treatment protocol based on its physicochemical stability

Objetivo: La administración intrapleural de fibrinolíticos y dornasa alfa ha demostrado en estudios aleatorizados ser capaz de disminuir la necesidad de desbridamiento quirúrgico del empiema y los días de estancia media hospitalaria. Sin embargo, su aplicación en práctica clínica es limitada, probablemente debido a la falta de protocolos que simplifiquen su administración. El presente estudio tiene como objetivo analizar la estabilidad fisicoquímica de la administración simultánea de uroquinasa y dornasa alfa para el posterior desarrollo de un protocolo de uso en práctica clínica. Método: Ensayo de estabilidad in vitro de uroquinasa, dornasa alfa y la mezcla de ambos. Se evaluó su estabilidad como (i) ausencia de partículas, (ii) variación de color y (iii) cambios de pH a tiempos 0,30 minutos, 1, 2 y 4 horas a 37°C. Cada muestra se preparó y analizó por triplicado. Resultados: Las soluciones individuales de uroquinasa y dornasa alfa mostraron cambios ligeros del pH, sin cambios en su color ni presencia de partículas en suspensión. La mezcla de uroquinasa y dornasa alfa no fue estable transcurridas 2 horas, mostrando turbidez por la floculación y separación de fases con formación de precipitado a las 4 horas. Se desarrolló un protocolo de uso clínico basado en la administración secuencial de uroquinasa y dornasa alfa, ya que no fue posible garantizar la estabilidad fisicoquímica de la administración simultánea de ambos fármacos. Conclusiones: Los datos de estabilidad fisicoquímica no permiten asegurar la administración simultánea de ambos fármacos de manera segura y eficaz, por lo que se propone un protocolo de administración secuencial

Objective: Intrapleural administration of fibrinolytics and dornase alfa has been shown in randomized studies to be able to reduce both the need for surgical debridement of empyema and the average hospital stay. However, its application in clinical practice is limited, probably due to the lack of protocols that simplify its administration. The present study aims to analyze the physicochemical stability of the simultaneous urokinase and dornase alfa administration for the subsequent development of a clinical practice use protocol. Method: In vitro stability test of urokinase, dornase alfa and a combination of both. Its stability was evaluated as (i) absence of particles, (ii) color variation and (iii) pH changes at times 0,30 minutes, 1,2 and 4 hours at 37°C. Each sample was prepared and analyzed in triplicate. Results: Individual solutions of urokinase and dornase alfa showed slight changes in pH, finding no changes in either color or presence of suspended particles. The urokinase and dornase alfa combination was not stable after 2 hours, when turbidity emerged due to flocculation and phase separation. After 4 hours, precipitate formation was found. A protocol for clinical use was developed based on urokinase and dornase alfa sequential administration, since it was not possible to guarantee the physicochemical stability of the simultaneous administration of both drugs. Conclusions: The physicochemical stability data obtained does not allow to ensure a simultaneous administration of both drugs in a safe and effective way, thus a sequential administration protocol is proposed

Exposure-response modeling of tocilizumab in rheumatoid arthritis using continuous composite measures and their individual components.

AIMS: Tocilizumab has a direct effect on inflammatory markers. Therefore, composite measures for disease activity assessment in rheumatoid arthritis (RA) using these inflammatory markers may not be suitable for tocilizumab treatment. We used a modelling approach to describe the tocilizumab exposure-response relationship and to investigate the different dynamics of the individual components of the routinely used continuous composite measures. METHODS: Pharmacokinetic (PK), clinical and laboratory data were obtained from a prospective, observational, single-centre study involving 35 subjects with RA treated with intravenous tocilizumab. A population PK/pharmacodynamic analysis was performed using nonlinear mixed effects models. RESULTS: The population for model development comprised 1086, 1083 and 1082 observations calculated with the disease activity score based on 28 joint (DAS28) and the simplified and clinical disease activity scores (SDAI, CDAI). The tocilizumab exposure-response relationship was described with an indirect-response model. Two main groups of individual components were identified based on their different dynamics under tocilizumab treatment: (i) tender and swollen joint counts and patient and evaluator global assessment showed a slower decrease of their baseline value (half-life: 4.6 weeks, RSE: 24%) and the need for higher serum drug concentration (EC50 : 4.60 µg/mL, RSE: 103%, IIV: 359%) than (ii) C-reactive protein and erythrocyte sedimentation rate (half-life: 2.3 weeks, RSE 19%; EC50 : 0.878 µg/mL, RSE: 41%, IIV: 238%). CONCLUSION: Our study confirms a different dynamics of the individual components of the most frequently used continuous composite measures under tocilizumab treatment which should be taken into account to avoid misassessment of disease activity.

Sequential intrapleural administration of fibrinolytic drugs and dornase alfa for empyema management. Treatment protocol based on its physicochemical stability.

OBJECTIVE: Intrapleural administration of fibrinolytics and dornase alfa has been shown in randomized studies to be able to reduce both the  need for surgical debridement of empyema and the average  hospital stay. However, its application in clinical practice is limited,  probably due to the lack of protocols that simplify its administration. The  present study aims to analyze the physicochemical stability of the  simultaneous urokinase and dornase alfa administration for the  subsequent development of a clinical practice use protocol. METHOD: In vitro stability test of urokinase, dornase alfa and a  combination of both. Its stability was evaluated as (i) absence of  particles, (ii) color variation and (iii) pH changes at times 0, 30 minutes,  1, 2 and 4 hours at 37 °C. Each sample was prepared and  analyzed in triplicate. RESULTS: Individual solutions of urokinase and dornase alfa showed slight changes in pH, finding no changes in either color or  presence of suspended particles. The urokinase and dornase alfa  combination was not stable after 2 hours, when turbidity emerged due  to flocculation and phase separation. After 4 hours, precipitate  formation was found. A pro tocol for clinical use was developed based on  urokinase and dornase alfa sequential administration, since it was  not possible to guarantee the physicochemical stability of the simultaneous administration of both drugs. CONCLUSIONS: The physicochemical stability data obtained does not allow to ensure a simultaneous administration of both drugs in a  safe and effective way, thus a sequential administration protocol is  proposed.

Objetivo: La administración intrapleural de fibrinolíticos y dornasa alfa ha demostrado en estudios aleatorizados ser capaz de disminuir la  necesidad de desbridamiento quirúrgico del empiema y los días de  estancia media hospitalaria. Sin embargo, su aplicación en práctica  clínica es limitada, probablemente debido a la falta de protocolos que  simplifiquen su administración. El presente estudio tiene como objetivo  analizar la estabilidad fisicoquímica de la administración simultánea de  uroquinasa y dornasa alfa para el posterior desarrollo de un protocolo de  uso en práctica clínica.Método: Ensayo de estabilidad in vitro de uroquinasa, dornasa alfa y la  mezcla de ambos. Se evaluó su estabilidad como (i) ausencia de partículas, (ii) variación de color y (iii) cambios de pH a tiempos 0,  30 minutos, 1, 2 y 4 horas a 37 °C. Cada muestra se preparó y analizó  por triplicado.Resultados: Las soluciones individuales de uroquinasa y dornasa alfa mostraron cambios ligeros del pH, sin cambios en su color ni  presencia de partículas en suspensión. La mezcla de uroquinasa y  dornasa alfa no fue estable transcurridas 2 horas, mostrando turbidez  por la floculación y sepa ración de fases con formación de precipitado a  las 4 horas. Se desarrolló un protocolo de uso clínico basado en la  administración secuencial de uroquinasa y dornasa alfa, ya que no fue  posible garantizar la estabilidad fisicoquímica de la administración  simultánea de ambos fármacos.Conclusiones: Los datos de estabilidad fisicoquímica no permiten  asegurar la administración simultánea de ambos fármacos de manera  segura y eficaz, por lo que se propone un protocolo de administración  secuencial.

Tocilizumab in the treatment of adult rheumatoid arthritis.

Rheumatoid arthritis (RA) is the most prevalent immune-mediated chronic rheumatic disease and is associated with joint destruction and disability. Therapeutic strategies, including biological disease-modifying antirheumatic drugs (bDMARDs) have improved the prognosis and quality of life of RA patients. Tocilizumab (TCZ) is a humanized monoclonal antibody against IL-6 receptor licensed in 2009 that has demonstrated clinical efficacy in various adult RA populations. RA management guidelines and recommendations consider TCZ as one of the bDMARDS indicated after methotrexate or other conventional synthetic DMARDs and/or TNF inhibitors failure in adult RA. Of particular interest is the demonstration of its effectiveness in monotherapy in comparison with other bDMARDs. Recent observational studies have shown good results for the safety profile of TCZ with no new alert signals.

Fixed dosing of intravenous tocilizumab in rheumatoid arthritis. Results from a population pharmacokinetic analysis.

AIMS: Intravenous tocilizumab is currently dosed on body weight, although a weak correlation between body weight and clearance has been described. The aim of the study was to assess the current dosing strategy and provide a scientific rational for dosing using a modelling and simulation approach. METHODS: Serum concentrations and covariates were obtained from intravenous tocilizumab treated subjects at a dose of 4, 6 or 8 mg every 28 days. A population pharmacokinetic analysis was performed using nonlinear mixed effects modelling. The final model was used to simulate tocilizumab exposure to assess a dosing strategy based on body weight or fixed dosing, using as target a cumulative area under the curve at 24 weeks of treatment above 100 × 103  µg h ml-1 . RESULTS: A one-compartment disposition model with parallel linear and nonlinear elimination best described the concentration-time data. The typical population mean values for clearance, apparent volume of distribution, maximum elimination rate and Michaelis-Menten constant were 0.0104 l h-1 , 4.83 l, 0.239 mg h-1 and 4.22 µg ml-1 , respectively. Interindividual variability was included for clearance (17.0%) and volume of distribution (30.8%). Significant covariates for clearance were patient body weight and C-reactive protein serum levels. An estimated exponent for body weight of 0.360 confirms the weak relationship with tocilizumab clearance. Simulations demonstrate that patients with lower weights are at risk of underdosing if the weight-based dosing approach is used. However, fixed-dosing provides a more consistent drug exposure regardless of weight category. CONCLUSIONS: Our study provides evidence to support fixed dosing of intravenous tocilizumab in rheumatoid arthritis patients since it reduces variability in tocilizumab exposure among weight categories compared to the current weight-based dosing approach.