Bioequivalence studies with anti-TNF biosimilars

Introduction: Biosimilars, as defined by the European Medicines Agency, have been used in Europe since 2006. The landscape was considerably expanded when the first biosimilar of a monoclonal was approved and introduced in the European market. CT-P13 was developed by Celltrion as an infliximab biosimilar in 2013, not without controversy. As these complex molecules cannot be completely identical, some experts, clinicians, and even patients were skeptical regarding the real bioequivalence of the drugs. Currently, several new infliximab and adalimumab biosimilars are available or will reach the market in a few months. Areas covered: Our goal is to review, mainly from a clinical perspective, the available evidence for bioequivalence of anti-TNF biosimilars. We aim to take into account not only preclinical studies, mostly done for regulatory issues, but also data from clinical studies. Expert opinion: We can conclude that bioequivalence with originator is well demonstrated in those drugs which have followed European Medicines Agency regulatory pathways. Switching from originator to biosimilar appears safe for all indications. However, there are few data available for switching from one biosimilar to another, or for complete interchangeability. Prospective studies and strict pharmacovigilance are recommended

Polypharmacy in older adults with human immunodeficiency virus infection compared with the general population

Background: The percentage of older HIV-positive patients is growing, with an increase in age-related comorbidities and concomitant medication. Objectives: To quantify polypharmacy and profile types of non-antiretroviral drugs collected at community pharmacies in 2014 by HIV-positive individuals on antiretroviral therapy and to compare these findings with those of the general population. Methods: HIV-positive patients (n=199) were compared with a group of patients from the general population (n=8, 172), aged between 50 and 64 years. The factors compared were prevalence of polypharmacy (=5 comedications with cumulative defined daily dose DDD] per drug over 180), percentage of patients who collected each therapeutic class of drug, and median duration for each drug class (based on DDD). Results were stratified by sex. Results: Polypharmacy was more common in HIV-positive males than in the male general population (8.9% vs 4.4%, P=0.010). Polypharmacy was also higher in HIV-positive females than in the female general population (11.3% vs 3.4%, P=0.002). Percentage of HIV-positive patients receiving analgesics, anti-infectives, gastrointestinal drugs, central nervous system (CNS) agents, and respiratory drugs was higher than in the general population, with significant differences between male populations. No differences were observed in proportion of patients receiving cardiovascular drugs. The estimated number of treatment days (median DDDs) were higher in HIV-positive males than in males from the general population for anti-infectives (32.2 vs 20.0, P<0.001) and CNS agents (238.7 vs 120.0, P=0.002). A higher percentage of HIV-positive males than males from the general population received sulfonamides (17.1% vs 1.5%, P, 0.001), macrolides (37.1% vs 24.9%, P=0.020), and quinolones (34.3% vs 21.2%, P=0.009). Conclusion: Polypharmacy is more common in HIV-positive older males and females than in similarly aged members of the general population. HIV-positive patients received more CNS drugs and anti-infectives, specifically sulfonamides, macrolides, and quinolones, but there were no differences in the percentage of patients receiving cardiovascular drugs. It is essential to investigate nonantiretroviral therapy medication use in the HIV-positive population to ensure these patients receive appropriate management

Comparative Evaluation of Three Automated Systems for DNA Extraction in Conjunction with Three Commercially Available Real-Time PCR Assays for Quantitation of Plasma Cytomegalovirus DNAemia in Allogeneic Stem Cell Transplant Recipients▿

Limited data are available on the performance of different automated extraction platforms and commercially available quantitative real-time PCR (QRT-PCR) methods for the quantitation of cytomegalovirus (CMV) DNA in plasma. We compared the performance characteristics of the Abbott mSample preparation system DNA kit on the m24 SP instrument (Abbott), the High Pure viral nucleic acid kit on the COBAS AmpliPrep system (Roche), and the EZ1 Virus 2.0 kit on the BioRobot EZ1 extraction platform (Qiagen) coupled with the Abbott CMV PCR kit, the LightCycler CMV Quant kit (Roche), and the Q-CMV complete kit (Nanogen), for both plasma specimens from allogeneic stem cell transplant (Allo-SCT) recipients (n = 42) and the OptiQuant CMV DNA panel (AcroMetrix). The EZ1 system displayed the highest extraction efficiency over a wide range of CMV plasma DNA loads, followed by the m24 and the AmpliPrep methods. The Nanogen PCR assay yielded higher mean CMV plasma DNA values than the Abbott and the Roche PCR assays, regardless of the platform used for DNA extraction. Overall, the effects of the extraction method and the QRT-PCR used on CMV plasma DNA load measurements were less pronounced for specimens with high CMV DNA content (>10,000 copies/ml). The performance characteristics of the extraction methods and QRT-PCR assays evaluated herein for clinical samples were extensible at cell-based standards from AcroMetrix. In conclusion, different automated systems are not equally efficient for CMV DNA extraction from plasma specimens, and the plasma CMV DNA loads measured by commercially available QRT-PCRs can differ significantly. The above findings should be taken into consideration for the establishment of cutoff values for the initiation or cessation of preemptive antiviral therapies and for the interpretation of data from clinical studies in the Allo-SCT setting

Predictive model of pheochromocytoma based on the imaging features of the adrenal tumours

The purpose of our study was to develop a predictive model to rule out pheochromocytoma among adrenal tumours, based on unenhanced computed tomography (CT) and/or magnetic resonance imaging (MRI) features. We performed a retrospective multicentre study of 1131 patients presenting with adrenal lesions including 163 subjects with histological confirmation of pheochromocytoma (PHEO), and 968 patients showing no clinical suspicion of pheochromocytoma in whom plasma and/or urinary metanephrines and/or catecholamines were within reference ranges (non-PHEO). We found that tumour size was significantly larger in PHEO than non-PHEO lesions (44.3 +/- 33.2 versus 20.6 +/- 9.2 mm respectively; P < 0.001). Mean unenhanced CT attenuation was higher in PHEO (52.4 +/- 43.1 versus 4.7 +/- 17.9HU; P < 0.001). High lipid content in CT was more frequent among non-PHEO (83.6% versus 3.8% respectively; P < 0.001); and this feature alone had 83.6% sensitivity and 96.2% specificity to rule out pheochromocytoma with an area under the receiver operating characteristics curve (AUC-ROC) of 0.899. The combination of high lipid content and tumour size improved the diagnostic accuracy (AUC-ROC 0.961, sensitivity 88.1% and specificity 92.3%). The probability of having a pheochromocytoma was 0.1% for adrenal lesions smaller than 20 mm showing high lipid content in CT. Ninety percent of non-PHEO presented loss of signal in the out of phase MRI sequence compared to 39.0% of PHEO (P < 0.001), but the specificity of this feature for the diagnosis of non-PHEO lesions low. In conclusion, our study suggests that sparing biochemical screening for pheochromocytoma might be reasonable in patients with adrenal lesions smaller than 20 mm showing high lipid content in the CT scan, if there are no typical signs and symptoms of pheochromocytoma

Implante hematopoyético de una serie de pacientes movilizados con Plerixafor. Estudio retrospectivo multicéntrico

Poster [PC-256] Introducción: Plerixafor (PLX) es un inhibidor del receptor CXCR4 de probada eficacia en la recolección de PHSP para autotrasplante hematopoyético (TASPE) en pacientes malos movilizadores. Los estudios llevados a cabo hasta la fecha se han centrado mayoritariamente en aspectos referentes a la cinética de movilización (Mx) y rendimiento. El objetivo de nuestro estudio es recoger una amplia experiencia multicéntrica sobre el injerto hematopoyético a corto y medio plazo de pacientes que habían sido movilizados con PLX. Paciente: s y Métodos: Estudiamos retrospectivamente todos los pacientes que recibieron PLX como parte del esquema de movilización de PHSP para TASPE durante los años 2008-18 en siete hospitales de la zona norte; las enfermedades de base fueron: 94 linfomas no Hogdkin, 14 con enfermedad de Hogdkin, 78 mieloma múltiple y 4 con otros diagnósticos. 108 pacientes eran varones (56%) y 82 mujeres (44%). Su edad mediana era 59 años (4-73). Su peso y su altura oscilaron entre 15-134 kg y 106-188 cm, respectivamente. La mediana de líneas de tratamiento de nuestra serie fue de 2 (1-5); veintiún pacientes habían recibido radioterapia extensa y 15 pacientes uno o varios TASPEs previos. El número de intentos de Mx previos osciló entre 0 y 4 (mediana: 1). La pauta de G-CSF empleada fue de 5-10 mcg/kg/12 h durante 1-14 días (mediana: 6 días) y la dosis de PLX fue la recomendada en ficha técnica (0.24mcg/Kg/24horas). En 36 casos (18, 95%) la movilización se realizó en la fase de recuperación tras un ciclo de la quimioterapia de tratamiento. Tabla 1. Características de la serie y empleo de PLX. Resultados: se realizaron un total de 159 TASPEs. El estatus de la hemopatía en el momento del trasplante era remisión completa en el 50% de los casos. En cuanto a los resultados de movilización y colecta, la mediana de sesiones de aféresis requeridas fue de 2, rango (0-5) y la cifra de células CD34+ recolectada fue de 2, 79 (x 106/kg) con un rango entre 0 y 30, 3. Tabla 2. Datos de implante a corto y medio plazo Conclusiones: 1) el empleo de Plerixafor permitió realizar el TASPE en un alto porcentaje de pacientes malos movilizadores; 2) la calidad del injerto a corto y medio plazo de los pacientes autotrasplantados movilizados con PLX fue óptimo en la gran mayoría de los casos; 3) en nuestro conocimiento, esta serie multicéntrica es una de las mayores comunicadas enfocada en la calidad del implante a corto y medio plazo de pacientes malos movilizadores sometidos a TASPE

Monitorización del consumo de sustancias de abuso legales e ilegales en España a través de las aguas residuales en el marco de la red ESAR-Net

Trabajo presentado en el 4th Congreso Internacional y XLIX Jornadas Nacionales de Socidrogalcohol - VIII Congreso Nacional Patología Bio-Psicosocial, celebrado en Tenerife del 06 al 08 de octubre de 2022

Prospective Observational Study of Pazopanib in Patients with Advanced Renal Cell Carcinoma (PRINCIPAL Study)

Background: Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC). Subjects, Materials, and Methods: Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups. Results: Six hundred fifty-seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2–12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups. Conclusion: PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting. Implications for Practice: PRINCIPAL is the largest (n = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors’ knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real-world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first-line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months

Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant Escherichia coli Bacteremic Urinary Tract Infections

IMPORTANCE The consumption of broad-spectrum drugs has increased as a consequence of the spread of multidrug-resistant (MDR) Escherichia coli. Finding alternatives for these infections is critical, for which some neglected drugs may be an option. OBJECTIVE To determine whether fosfomycin is noninferior to ceftriaxone or meropenem in the targeted treatment of bacteremic urinary tract infections (bUTIs) due to MDR E coli. DESIGN, SETTING, AND PARTICIPANTS This multicenter, randomized, pragmatic, open clinical trial was conducted at 22 Spanish hospitals from June 2014 to December 2018. Eligible participants were adult patients with bacteremic urinary tract infections due to MDR E coli; 161 of 1578 screened patients were randomized and followed up for 60 days. Data were analyzed in May 2021. INTERVENTIONS Patients were randomized 1 to 1 to receive intravenous fosfomycin disodium at 4 g every 6 hours (70 participants) or a comparator (ceftriaxone or meropenem if resistant; 73 participants) with the option to switch to oral fosfomycin trometamol for the fosfomycin group or an active oral drug or pa renteral ertapenem for the comparator group after 4 days. MAIN OUTCOMES AND MEASURES The primary outcome was clinical and microbiological cure (CMC) 5 to 7 days after finalization of treatment; a noninferiority margin of 7% was considered. RESULTS Among 143 patients in the modified intention-to-treat population (median [IQR] age, 72 [62-81] years; 73 [51.0%] women), 48 of 70 patients (68.6%) treated with fosfomycin and 57 of 73 patients (78.1%) treated with comparators reached CMC (risk difference, -9.4 percentage points; 1-sided 95% CI, -21.5 to infinity percentage points; P = .10). While clinical or microbiological failure occurred among 10 patients (14.3%) treated with fosfomycin and 14 patients (19.7%) treated with comparators (risk difference, -5.4 percentage points; 1-sided 95% CI. -infinity to 4.9; percentage points; P = .19), an increased rate of adverse event-related discontinuations occurred with fosfomycin vs comparators (6 discontinuations [8.5%] vs 0 discontinuations; P = .006). In an exploratory analysis among a subset of 38 patients who underwent rectal colonization studies, patients treated with fosfomycin acquired a new ceftriaxone-resistant or meropenem-resistant gram-negative bacteria at a decreased rate compared with patients treated with comparators (0 of 21 patients vs 4 of 17 patients [23.5%]; 1-sided P = .01). CONCLUSIONS AND RELEVANCE This study found that fosfomycin did not demonstrate noninferiority to comparators as targeted treatment of bUTI from MDR E coli; this was due to an increased rate of adverse event-related discontinuations. This finding suggests that fosfomycin may be considered for selected patients with these infections

Spread of a SARS-CoV-2 variant through Europe in the summer of 2020.

Following its emergence in late 2019, the spread of SARS-CoV-21,2 has been tracked by phylogenetic analysis of viral genome sequences in unprecedented detail3–5. Although the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced. However, travel within Europe resumed in the summer of 2020. Here we report on a SARS-CoV-2 variant, 20E (EU1), that was identified in Spain in early summer 2020 and subsequently spread across Europe. We find no evidence that this variant has increased transmissibility, but instead demonstrate how rising incidence in Spain, resumption of travel, and lack of effective screening and containment may explain the variant’s success. Despite travel restrictions, we estimate that 20E (EU1) was introduced hundreds of times to European countries by summertime travellers, which is likely to have undermined local efforts to minimize infection with SARS-CoV-2. Our results illustrate how a variant can rapidly become dominant even in the absence of a substantial transmission advantage in favourable epidemiological settings. Genomic surveillance is critical for understanding how travel can affect transmission of SARS-CoV-2, and thus for informing future containment strategies as travel resumes. © 2021, The Author(s), under exclusive licence to Springer Nature Limited