Bioequivalence assessment of high-capacity polymeric micelle nanoformulation of paclitaxel and Abraxane® in rodent and non-human primate models using a stable isotope tracer assay.

The in vivo fate of nanoformulated drugs is governed by the physicochemical properties of the drug and the functionality of nanocarriers. Nanoformulations such as polymeric micelles, which physically encapsulate poorly soluble drugs, release their payload into the bloodstream during systemic circulation. This results in three distinct fractions of the drug-nanomedicine: encapsulated, protein-bound, and free drug. Having a thorough understanding of the pharmacokinetic (PK) profiles of each fraction is essential to elucidate mechanisms of nanomedicine-driven changes in drug exposure and PK/PD relationships pharmacodynamic activity. Here, we present a comprehensive preclinical assessment of the poly (2-oxazoline)-based polymeric micelle of paclitaxel (PTX) (POXOL hl-PM), including bioequivalence comparison to the clinically approved paclitaxel nanomedicine, Abraxane®. Physicochemical characterization and toxicity analysis of POXOL hl-PM was conducted using standardized protocols by the Nanotechnology Characterization Laboratory (NCL). The bioequivalence of POXOL hl-PM to Abraxane® was evaluated in rats and rhesus macaques using the NCL's established stable isotope tracer ultrafiltration assay (SITUA) to delineate the plasma PK of each PTX fraction. The SITUA study revealed that POXOL hl-PM and Abraxane® had comparable PK profiles not only for total PTX but also for the distinct drug fractions, suggesting bioequivalence in given animal models. The comprehensive preclinical evaluation of POXOL hl-PM in this study showcases a series of widely applicable standardized studies by NCL for assessing nanoformulations prior to clinical investigation.

Carboplatin plus weekly nanoparticle albumin-bound paclitaxel in elderly patients with previously untreated advanced squamous non-small-cell lung cancer selected based on Mini Nutritional Assessment short-form scores: a multicenter phase 2 study.

PURPOSE: This multicenter, single-arm, open-label, phase 2 study assessed the efficacy and safety of carboplatin plus weekly nanoparticle albumin-bound paclitaxel in elderly patients with previously untreated advanced squamous non-small-cell lung cancer, selected based on the Mini Nutritional Assessment short-form scores (MNA-SF). METHODS: Patients received carboplatin (area under the curve: 6) on Day 1, and nanoparticle albumin-bound paclitaxel (100 mg/m2) on Days 1, 8, and 15, every 28 days for ≤4 cycles. Eligibility criteria included an MNA-SF score of ≥8 points. The primary endpoint was the objective response rate. RESULTS: Thirty patients with a median age of 76 (range 70-83) years were enrolled. The objective response rate was 50.0% (95% confidence interval: 31.3-68.7%), which met the primary objective of this study. The disease control rate was 73.3% (95% CI: 54.1-87.7%). At a median follow-up of 15.0 months, the median progression-free and overall survival was 7.1 and 19.1 months, respectively. The most common treatment-related adverse event of Grade ≥3 was neutropenia (66.7%). Non-hematological adverse events of Grade ≥3 were minor. Well-nourished patients, based on the MNA-SF, experienced fewer adverse events of Grade ≥3 compared to patients at risk of malnutrition. All treatment-related adverse events were tolerable and reversible. There were no treatment-related deaths. CONCLUSIONS: Carboplatin plus weekly nanoparticle albumin-bound paclitaxel is effective and well tolerated as a first-line treatment for elderly patients with advanced squamous non-small-cell lung cancer. Eligibility based on MNA-SF screening may be useful in determining acceptable toxicity.

A Platform for Rapid, Quantitative Assessment of Multiple Drug Combinations Simultaneously in Solid Tumors In Vivo.

While advances in high-throughput screening have resulted in increased ability to identify synergistic anti-cancer drug combinations, validation of drug synergy in the in vivo setting and prioritization of combinations for clinical development remain low-throughput and resource intensive. Furthermore, there is currently no viable method for prospectively assessing drug synergy directly in human patients in order to potentially tailor therapies. To address these issues we have employed the previously described CIVO platform and developed a quantitative approach for investigating multiple combination hypotheses simultaneously in single living tumors. This platform provides a rapid, quantitative and cost effective approach to compare and prioritize drug combinations based on evidence of synergistic tumor cell killing in the live tumor context. Using a gemcitabine resistant model of pancreatic cancer, we efficiently investigated nine rationally selected Abraxane-based combinations employing only 19 xenografted mice. Among the drugs tested, the BCL2/BCLxL inhibitor ABT-263 was identified as the one agent that synergized with Abraxane® to enhance acute induction of localized apoptosis in this model of human pancreatic cancer. Importantly, results obtained with CIVO accurately predicted the outcome of systemic dosing studies in the same model where superior tumor regression induced by the Abraxane/ABT-263 combination was observed compared to that induced by either single agent. This supports expanded use of CIVO as an in vivo platform for expedited in vivo drug combination validation and sets the stage for performing toxicity-sparing drug combination studies directly in cancer patients with solid malignancies.

Nab-paclitaxel (Abraxane) para el tratamiento del cáncer de páncreas metastásico / Nab-paclitaxelfor the treatment of metastatic pancreatic cancer

CONTEXTO CLÍNICO: El cáncer de páncreas es la octava causa de muerte oncológica en el mundo. De acuerdo a valores del año 2012, en Argentina, hubo 3,988 casos, con una incidencia anual de 9,7% y una mortalidad de 10,5%. La población afectada abarca en su mayoría hombres mayores de 60 años. Los factores de riesgo que se asocian a su desarrollo incluyen el tabaquismo, la pancreatitis crónica, los antecedentes familiares, la obesidad y la diabetes tipo I y II. Dado que el cáncer de páncreas no genera síntomas en etapas tempranas, en general se diagnostica en etapas avanzadas. La mayoría de los cánceres de páncreas (>70%) comienzan en la cabeza del páncreas y los síntomas son secundarios a la compresión que generan (ictericia indolora, dolor abdominal o lumbar inespecífico, coluria); el resto de los tumores de páncreas se localizan en la cola y se presentan tardíamente con dolor abdominal y signos de enfermedad metastásica. La duodenopancratectomía es la única opción curativa, ésta sólo es posible en pacientes que cumplen con los criterios de resecabilidad (etapas tempranas, I y II) y que no posean comorbilidades asociadas. En los pacientes con lesiones inoperables, las metas de tratamiento son aliviar síntomas y prolongar la vida. En pacientes con metástasis, la expectativa de vida a los cinco años es de sólo el 2%, son incurables, y el tratamiento de elección para estos pacientes es la quimioterapia. Adicionalmente a esto, los pacientes pueden recibir tratamiento paliativo para aliviar el dolor y/o para descomprimir la vía biliar (bypass biliar), o recibir quimioterapia de acuerdo al estado funcional medido, por ejemplo, con las escalas ECOG o KPS. Estas mediciones de estado funcional tratan de cuantificar el estado general de los pacientes con cáncer de acuerdo a las actividades diarias que pueden realizar, y van desde valores de 100 (sin evidencia de enfermedad) hasta 0 (muerte); a un paciente que puede ocuparse de su cuidado personal pero que no puede desarrollar actividades habituales como trabajar, se le asigna un valor de 70 en la escala KPS. Dentro de las opciones quimioterapéuticas, Gemcitabine junto con Nab-paclitaxel (Abraxane) o el esquema FOLFIRINOX (leucovorina, 5-Fluorouracil, irinotecan, oxaliplatino) son la alternativa de tratamiento más estudiadas para este grupo de pacientes y para su uso se evalúa el impacto en la sobrevida global, tiempo libre de progresión de enfermedad y eventos adversos que afectan la calidad de vida. La formulación de quimioterápicos combinados como FOLFIRINOX ha sido sólo evaluada en pacientes con buen estado funcional y sin comorbilidades debido a su alta toxicidad, por lo que se propone el esquema Gemcitabine + Nab-Paclitaxel (Gem+Nab-P) como opción terapéutica a pacientes con regular estado funcional (KPS 70) y de más de 75 años con comorbilidades. TECNOLOGÍA: El Nab-paclitaxel pertenece a la familia de los taxanos. Es una formulación de paclitaxel unida a albúmina (nab-paclitaxel) creada para mejorar los problemas de insolubilidad en las formulaciones previas. OBJETIVO: Evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura de Nab-paclitaxel para el tratamiento de cáncer de páncreas metastásico. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas (incluyendo Medline, Cochrane y CRD), en buscadores genéricos de Internet, agencias de evaluación de tecnologías sanitarias y financiadores de salud utilizando la siguiente estrategia: ((((Pancreatic Neoplasms [tiab] OR Pancreatic Neoplasms [MeSH] or Pancreatic adenoma [Supplementary Concept] OR Pancreatic cancer [tiab] OR metastatic pancreatic cancer [tiab] OR advanced pancreatic cancer [tiab] OR metastatic pancreatic adenocarcinoma [tiab] OR Pancreatic adenoma [Supplementary Concept]) AND (Paclitaxel[Mesh] or 130-nm albumin-bound paclitaxel [Supplementary Concept] OR nab-paclitaxel [tiab] OR paclitaxel [tiab] or Abraxane [tiab] OR "Nanoparticle albumin-bound-paclitaxel" [tiab])))). Se priorizó la inclusión de revisiones sistemáticas (RS), ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias y económicas, guías de práctica clínica (GPC) y políticas de cobertura de otros sistemas de salud cuando estaban disponibles. RESULTADOS: Para el siguiente informe se incluyeron una revisión sistemática incluida en un informe de ETS, un meta-análisis en red, una serie de casos para evaluar dosis letal, una guía de práctica clínica y un subanálisis de un ECA para evaluar sobrevida asociado a calidad de vida, así como siete políticas de cobertura de financiadores de servicios de salud. CONCLUSIONES: Se encontró escasa evidencia, de buena calidad metodológica. En el tratamiento del cáncer de páncreas metastásico en pacientes que no pueden recibir FOLFIRINOX, el uso de Nab-Paclitaxel asociado a Gemcitabine como tratamiento de elección podría mejorar la sobrevida global en menos de tres meses en comparación con Gemcitabine solo aunque con una mayor incidencia de eventos adversos. No se hallaron estudios que compararan a FOLFIRINOX con Nab-Paclitaxel asociado a Gemcitabine. No existe consenso sobre su uso en las políticas de cobertura relevada debido a su alto costo y reducido beneficio clínico.

Cost-utility analysis of nanoparticle albumin-bound paclitaxel versus paclitaxel in monotherapy in pretreated metastatic breast cancer in Spain.

AIM: The COSTABRAX study evaluated the cost-effectiveness of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) versus polyethylated castor oil-based standard paclitaxel (sb-paclitaxel) in the treatment of patients with previously treated metastatic breast cancer in Spain. MATERIALS & METHODS: Efficacy data were obtained from the CA012 trial (nab-paclitaxel administered every 3 weeks [q3w] and sb-paclitaxel q3w) and indirect comparison (sb-paclitaxel administered weekly), and were modeled to a time horizon of 5 years using a Markov model. The analysis was performed from the National Health Service perspective. Use of resources and key assumptions of the model were validated by a panel of 22 local oncologists. RESULTS: Compared with sb-paclitaxel q3w, nab-paclitaxel q3w was cost effective, with a cost per life year gained of €11,088 and a cost per quality-adjusted life year of €17,808. Compared with sb-paclitaxel administered weekly, it showed savings of €711 per patient. CONCLUSION: The COSTABRAX study showed that nab-paclitaxel q3w is a cost-effective alternative compared with sb-paclitaxel q3w and a cost-saving alternative to sb-paclitaxel administered weekly in Spain.

Albumin-bound paclitaxel (Abraxane) for advanced breast cancer.

A new formulation that should be safer and easier to administer than Taxol.