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Macrocyclic peptides (MCPs) are an emerging class of promising drug modalities that can be used to interrogate hard-to-drug ("undruggable") targets. However, their poor intestinal stability is one of the major liabilities or obstacles for oral drug delivery. We therefore investigated the metabolic stability and biotransformation of MCPs via a systematic approach and established an integrated in vitro assay strategy to facilitate MCP drug discovery, with a focus on oral delivery liabilities. A group of diverse MCPs were incubated with representative matrices, including simulated intestinal fluid with pancreatin (SIFP), human enterocytes, liver S9 fractions, liver lysosomes, plasma, and recombinant enzymes. The results revealed that the stability and biotransformation of MCPs varied, with the major metabolic pathways identified in different matrices. Under the given conditions, the selected MCPs generally showed better stability in plasma compared to that in SIFP. Our data suggest that pancreatic enzymes act as the primary metabolic barrier for the oral delivery of MCPs, mainly through hydrolysis of their backbone amide bonds. Whereas in enterocytes, multiple metabolic pathways appeared to be involved and resulted in metabolic reactions such as oxidation and reduction in addition to hydrolysis. Further studies suggested that lysosomal peptidase cathepsin B could be a major enzyme responsible for the cleavage of side-chain amide bonds in lysosomes. Collectively, we developed and implemented an integrated assay for assessing the metabolic stability and biotransformation of MCPs for compound screening in the discovery stage toward oral delivery. The proposed question-driven assay cascade can provide biotransformation insights that help to guide and facilitate lead candidate selection and optimization.
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Péptido Hidrolasas , Péptidos , Biotransformación , Descubrimiento de Drogas , Humanos , Preparaciones FarmacéuticasRESUMEN
Parenteral delivery remains a compelling drug delivery route for both large- and small-molecule drugs and can bypass issues encountered with oral absorption. For injectable drug products, there is a strong patient preference for subcutaneous administration due to its convenience over intravenous infusion. However, in subcutaneous injection, in contrast to intravenous administration, the formulation is in contact with an extracellular matrix environment that behaves more like a gel than a fluid. This can impact the expected performance of a formulation. Since typical bulk fluid dissolution studies do not accurately simulate the subcutaneous environment, improved in vitro models to help better predict the behavior of the formulation are critical. Herein, we detail the development of a new model system consisting of a more physiologically relevant gel phase to simulate the rate of drug release and diffusion from a subcutaneous injection site using agarose hydrogels as a tissue mimic. This is coupled with continuous real-time data collection to accurately monitor drug diffusion. We show how this in vitro model can be used as an in vivo performance differentiator for different formulations of both large and small molecules. Thus, this model system can be used to improve optimization and understanding of new parenteral drug formulations in a rapid and convenient manner.
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Sistemas de Liberación de Medicamentos , Sefarosa , Preparaciones de Acción Retardada , Difusión , Composición de Medicamentos/métodos , Liberación de Fármacos , Humanos , Hidrogeles/química , Hidrogeles/farmacología , Inyecciones Subcutáneas/métodos , Modelos Biológicos , Preparaciones Farmacéuticas/administración & dosificación , Sefarosa/química , Sefarosa/farmacologíaRESUMEN
The development of drug dispersions using solid lipids is a novel formulation strategy that can help address the challenges of poor drug solubility and systemic exposure after oral administration. The highly lipophilic and poorly water-soluble drug torcetrapib could be effectively formulated into solid lipid microparticles (SLMs) using an anti-solvent precipitation strategy. Acoustic milling was subsequently used to obtain solid lipid nanoparticles (SLNs). Torcetrapib was successfully incorporated into the lipid matrix in an amorphous state. Spherical SLMs with mean particle size of approximately 15-18 µm were produced with high drug encapsulation efficiency (>96%) while SLNs were produced with a mean particle size of 155 nm and excellent colloidal stability. The in vitro drug release and the in vivo absorption of the solid lipid micro- and nanoparticles after oral dosing in rats were evaluated against conventional crystalline drug powders as well as a spray dried amorphous polymer dispersion formulation. Interestingly, the in vitro drug release rate from the lipid particles could be tuned for immediate or extended release by controlling either the particle size or the precipitation temperature used when forming the drug-lipid particles. This change in the rate of drug release was manifested in vivo with changes in Tmax as well. In addition, in vivo pharmacokinetic studies revealed a significant increase (â¼6 to 11-fold) in oral bioavailability in rats dosed with the SLMs and SLNs compared to conventional drug powders. Importantly, this formulation approach can be performed rapidly on a small scale, making it ideal as a formulation technology for use early in the drug discovery timeframe.
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Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/farmacocinética , Portadores de Fármacos , Lípidos/química , Quinolinas/administración & dosificación , Quinolinas/farmacocinética , Administración Oral , Animales , Anticolesterolemiantes/sangre , Anticolesterolemiantes/química , Disponibilidad Biológica , Preparaciones de Acción Retardada , Composición de Medicamentos , Masculino , Modelos Biológicos , Nanopartículas , Tamaño de la Partícula , Quinolinas/sangre , Quinolinas/química , Ratas Wistar , Solubilidad , TemperaturaRESUMEN
Extemporaneous preparation (EP) formulation is an attractive strategy to accelerate the formulation development of new chemical entities for first entry into human study. In this work, an EP suspension formulation for a development drug candidate GDC-6599 was successfully developed. The formulation spanned a wide concentration range from 0.1 to 2.0 mg/mL. A non-solubilizing vehicle, 0.6 % (w/v) methylcellulose solution was used to suspend GDC-6599. An aversive agent denatonium benzoate at an extremely low level (6 ppm) was applied as a taste masking agent. This enabled a simple matrix for the analysis of related substances from GDC-6599 during all stability studies. Microcrystalline cellulose at 10 mg/mL concentration was added to the EP formulation to generate a suspension appearance, leading to the success of using a single placebo for matching active formulation at all concentrations. The developed formulation demonstrated excellent homogeneity, sufficient stability and passed microbiological enumeration test. Rinsing performance test demonstrated that greater than 99.8 % amount of drug was successfully recovered by rinsing with water twice, providing guidance for clinical dosing. Biopharmaceutical assessment was conducted by both in silico simulation and in vitro tests. Greater than 90 % bioaccessibility of the EP suspension formulation was obtained via an in vitro system mimicking the human gastrointestinal absorption, consistent with the result from the in silico modeling. The developed EP formulation was successfully used to support the early single ascending dose (SAD) cohorts of GDC-6599 Phase I clinical study. The formulation matrix and assessment workflow developed in this work are generalizable as a platform for EP formulation development of new chemical entities for early phase clinical studies.
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Celulosa , Absorción Gastrointestinal , Humanos , Composición de Medicamentos , Administración Oral , Percepción del Gusto , Estabilidad de MedicamentosRESUMEN
We were attracted to the therapeutic potential of inhibiting Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), a RING E3 ligase that plays a critical role in regulating the activation of T cells. However, given that only protein-protein interactions were involved, it was unclear whether inhibition by a small molecule would be a viable approach. After screening an â¼6 billion member DNA-encoded library (DEL) using activated Cbl-b, we identified compound 1 as a hit for which the cis-isomer (2) was confirmed by biochemical and surface plasmon resonance (SPR) assays. Our hit optimization effort was greatly accelerated when we obtained a cocrystal structure of 2 with Cbl-b, which demonstrated induced binding at the substrate binding site, namely, the Src homology-2 (SH2) domain. This was quite noteworthy given that there are few reports of small molecule inhibitors that bind to SH2 domains and block protein-protein interactions. Structure- and property-guided optimization led to compound 27, which demonstrated measurable cell activity, albeit only at high concentrations.
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Drug nanosuspensions offer a promising approach to improve bioavailability for poorly soluble drug candidates. Such formulations often necessitate the inclusion of an excipient to stabilize the drug nanoparticles. However, the rationale for the choice of the correct excipient for a given drug candidate remains unclear. To gain molecular insight into formulation design, this work first utilizes a molecular dynamics simulation to computationally investigate drug-excipient interactions for a number of combinations that have been previously studied experimentally. We find that hydrophobic interactions drive excipient adsorption to drug nanoparticles and that the fraction of polar surface area serves as a predictor for experimental measurements of nanosuspension stability. To test these ideas prospectively, we applied our model to an uncharacterized drug compound, GDC-0810. Our simulations predicted that a salt form of GDC-0810 would lead to more stable nanosuspensions than the neutral form; therefore, we tested the stability of salt GDC-0810 nanosuspensions and found that the salt form readily formed nanosuspensions even without the excipient. To avoid computationally expensive simulations in the future, we extended our model by showing that simple, two-dimensional properties of single drug molecules can be used to rationalize nanosuspension designs without simulations. In all, our work demonstrates how computational tools can provide molecular insight into drug-excipient interactions and aid in rational formulation design.
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The subcutaneous administration of therapeutic peptides would provide significant benefits to patients. However, subcutaneous injections are limited in dosing volume, potentially resulting in high peptide concentrations that can incur significant challenges with solubility limitations, high viscosity, and stability liabilities. Herein, we report on the discovery that low-shear resonant acoustic mixing can be used as a general method to prepare stable nanoparticles of a number of peptides of diverse molecular weights and structures in water without the need for extensive amounts of organic solvents or lipid excipients. This approach avoids the stability issues observed with typical high-shear, high-intensity milling methods. The resultant peptide nanosuspensions exhibit low viscosity even at high concentrations of >100 mg/mL while remaining chemically and physically stable. An example nanosuspension of cyclosporine nanoparticles was dosed in rats via a subcutaneous injection and exhibited sustained release behavior. This suggests that peptide nanosuspension formulations can be one approach to overcome the challenges with high-concentration peptide formulations.
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The pharmaceutical industry has been challenged by the increasing number of poorly soluble drug candidates, resulting in significant issues with obtaining sufficient absorption and bioavailability, risk of exposure variability, and difficulties in achieving a safe therapeutic index. Additionally, the rapid and precise dispensing of specific drug dosages is an important aspect that can enable personalized medicines for the patient. Herein, we report on the development of inkjet printing as a method for delivering precise quantities of poorly soluble drug molecules using commercially available equipment. Despite challenges due to low solubility making it difficult to prepare liquid solutions, stable suspensions of drug nanoparticles with the appropriate viscosity were successfully printed and dispensed onto a thin film suitable for delivery. The drug nanoparticles remained intact and could be reconstituted after printing, demonstrating that they remained stable and retained their advantageous particle size. This demonstrates that inkjet printing can be a practical and convenient approach for dispensing poorly soluble drug molecules when formulated as nanosuspensions.
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In this study, we evaluated the aerodynamic performance, dissolution, and permeation behavior of micronized fluticasone propionate (FP) and magnesium stearate (MgSt) binary mixtures. Micronized FP was dry mixed with 2% w/w MgSt using a tumble mixer and a resonant acoustic mixer (RAM) with and without heating. The mixing efficacy was determined by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) analysis. Additional techniques were used to determine powder properties such as the dynamic vapor sorption (DVS), particle size distribution (PSD) by laser diffraction light scattering, and particle surface properties by scanning electron microscope (SEM). The aerodynamic performance was studied by the next-generation impactor (NGI) using drug-loaded capsules in a PlastiApi® device. Physiochemical properties such as porosity, particle size distribution, and surface area of the formulations were studied with adsorption and desorption curves fitted to several well-known models including Brunauer-Emmett-Teller (BET), Barret Joyner Halenda (BJH), and the density functional theory (DFT). The dissolution behavior of the formulations collected on the transwell inserts incorporated into stages 3, 5, and 7 of the NGI with a membrane providing an air interface was evaluated. Drug permeability of formulations was assessed by directly depositing particles on Calu-3 cells at the air-liquid interface (ALI). Drug concentration was determined by LC-MS/MS. A better MgSt mixing on micronized FP particles was achieved by mixing with a RAM with and without heating than with a tumble mixer. A significant concomitant increase in the % of emitted dose and powder aerosol performance was observed after MgSt mixing. Formulation 4 (RAM mixing at room temperature) showed the highest rate of permeability and correlation with dissolution profile. The results show that the surface enrichment of hydrophobic MgSt improved aerosolization properties and the dissolution and permeability rate of micronized FP by reducing powder agglomerations. A simple low-shear acoustic dry powder mixing method was found to be efficient and substantially improved the powder aerosolization properties and enhanced dissolution and permeability rate.
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Inhaladores de Polvo Seco , Espectrometría de Masas en Tándem , Administración por Inhalación , Aerosoles , Cromatografía Liquida , Fluticasona , Tamaño de la Partícula , Permeabilidad , Polvos , Ácidos Esteáricos , Propiedades de SuperficieRESUMEN
A diverse set of drug and polymer combinations have been effectively evaluated utilizing a newly developed method called acoustic fusion to form amorphous solid dispersions (ASD) on the mg-scale, indicating that this approach is a general procedure that can be applied for ASD drug formulations. We have demonstrated the effectiveness of this acoustic fusion process by generating amorphous solid dispersions of various BCS class 2 and 4 drug candidates, including torcetrapib, itraconazole, and lopinavir, with a variety of polymer systems, including HPMCAS (L, M, and H), copovidone, Soluplus®, PEG1500, Vitamin-E TPGS, Kolliphor EL, and Eudragit, etc. Formulations of these ASD drug products demonstrated significantly elevated solubility of the drug substance compared to the solubility of the crystalline form of the drug. Acoustic fusion products using the model drug torcetrapib in either HPMCAS-LF, copovidoneâ¯+â¯Vitamin-E TPGS, or Soluplus®, exhibited enhanced supersaturation solubility in aqueous buffer in vitro compared to the drug in crystalline form, indicating that the acoustic fusion process resulted in an amorphous solid dispersion state similar to those formed in spray drying (SD) or hot melt extrusion (HME) processes. In vivo dosing of formulations of the acoustic fusion products in a rat pharmacokinetic study at a dose level of 10â¯mg/kg resulted in an improvement in exposures of approximately 8-fold by AUC(0-24) in comparison to a conventional suspension formulation of the drug material in crystalline form, thus validating the efficiency of this novel acoustic fusion approach for elevating the bioperformance in preclinical studies.
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Tecnología de Extrusión de Fusión en Caliente , Itraconazol , Acústica , Animales , Composición de Medicamentos , Ratas , SolubilidadRESUMEN
Spray dried amorphous solid dispersions (ASDs) stand as one of the most effective formulation strategies to address issues of low aqueous solubility when developing new chemical entities.An emerging research topic focusing on the formation of amorphous nanoparticles or nanodroplets from ASD formulations has attracted attention recently. These ASD nanoparticlescan be highly beneficial and able to further increase oral bioavailability. The incorporation of surfactants in ASD formulations has been shown to facilitate the formation of these nanoparticles. Therefore, understanding the mechanism of surfactant-promoted nanoparticle formation becomes critical for the rational design of ASD formulations. This work demonstrated the importance of inclusion of the surfactant within the ASD composition for nanoparticle formation. In contrast, when a surfactant is added externally (e.g., by inclusion in the dosing vehicle), only a limited degree of nanoparticle formation was observed even at the optimized surfactant-to-drug ratios. A variety of different surfactants were also assessed for understanding their impact on ASD nanoparticle formation. The spray drying systems containing nonionic surfactants, Tween 80 and Vitamin E TPGS, produced higher amounts of in situ ASD nanoparticles when compared to an anionic surfactant, sodium lauryl sulfate (SLS). The ASD nanoparticles produced by the Genentech developmental compound, GDC-0334, were highly stable and retained their original particle size and amorphous feature for at least 18 h under biorelevant conditions. The high degree of nanoparticle formation from spray dried GDC-0334 containing Tween 80 combined with the superior physical stability of the nanoparticles also translated to enhanced in vivo performance in a rat pharmacokinetics study.
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Nanopartículas , Tensoactivos , Animales , Tamaño de la Partícula , Ratas , Dodecil Sulfato de Sodio , SolubilidadRESUMEN
Optimization of a series of aryl urea RAF inhibitors led to the identification of type II pan-RAF inhibitor GNE-0749 (7), which features a fluoroquinazolinone hinge-binding motif. By minimizing reliance on common polar hinge contacts, this hinge binder allows for a greater contribution of RAF-specific residue interactions, resulting in exquisite kinase selectivity. Strategic substitution of fluorine at the C5 position efficiently masked the adjacent polar NH functionality and increased solubility by impeding a solid-state conformation associated with stronger crystal packing of the molecule. The resulting improvements in permeability and solubility enabled oral dosing of 7. In vivo evaluation of 7 in combination with the MEK inhibitor cobimetinib demonstrated synergistic pathway inhibition and significant tumor growth inhibition in a KRAS mutant xenograft mouse model.
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Neoplasias/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinonas/uso terapéutico , Quinasas raf/antagonistas & inhibidores , Animales , Azetidinas/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Perros , Combinación de Medicamentos , Sinergismo Farmacológico , Femenino , Humanos , Células de Riñón Canino Madin Darby , Ratones Desnudos , Estructura Molecular , Mutación , Compuestos de Fenilurea/química , Compuestos de Fenilurea/metabolismo , Piperidinas/uso terapéutico , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Quinazolinonas/química , Quinazolinonas/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasas raf/genética , Quinasas raf/metabolismoRESUMEN
Structure-based optimization of a set of aryl urea RAF inhibitors has led to the identification of Type II pan-RAF inhibitor GNE-9815 (7), which features a unique pyrido[2,3-d]pyridazin-8(7H)-one hinge-binding motif. With minimal polar hinge contacts, the pyridopyridazinone hinge binder moiety affords exquisite kinase selectivity in a lipophilic efficient manner. The improved physicochemical properties of GNE-9815 provided a path for oral dosing without enabling formulations. In vivo evaluation of GNE-9815 in combination with the MEK inhibitor cobimetinib demonstrated synergistic MAPK pathway modulation in an HCT116 xenograft mouse model. To the best of our knowledge, GNE-9815 is among the most highly kinase-selective RAF inhibitors reported to date.
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Suspensions of drug nanoparticles known as nanosuspensions have emerged as a successful enabling formulation approach for poorly soluble drug candidates. These nanoparticles typically require stabilization with specific polymer or surfactant excipients to prevent aggregation from occurring. This study demonstrates the necessity of formulating drug nanosuspensions with amphiphilic excipients possessing long hydrophobic alkyl or polymer block chains to produce stable nanoparticles. 28 different excipients and excipient combinations at various loadings were screened across the 3 drug compounds and their effectiveness, as characterized by the lowest excipient loading needed to stabilize a monodisperse drug suspension, is quantified as a function of various excipient parameters such as molecular weight, HLB value, CMC, H-bond donors and acceptors, and the length of the hydrophobic alkyl chains and polymer blocks within their molecular structure. Traditional characterization parameters (molecular weight, HLB value, and CMC) fail to predict excipient effectiveness. The conformational flexibility and length of the hydrophobic regions of amphiphilic excipients appears to be critical for effectiveness. This hypothesis was supported by molecular modeling studies to better understand the interactions between the excipients with the drug nanoparticle surface.
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Excipientes/química , Nanopartículas/química , Química Farmacéutica , Interacciones Hidrofóbicas e Hidrofílicas , Indometacina/química , Itraconazol/química , Modelos Moleculares , Naproxeno/química , Tamaño de la Partícula , SuspensionesRESUMEN
A chiral self-assembled M4L6 host assembly has been shown to be a suitable host for the supramolecular encapsulation of a series of guests in polar solvents, ranging from simple organic ammonium cations to more complex organometallic species. This molecular recognition process creates highly selective reactivity within the host cavity. In order to understand the factors driving the molecular recognition process, the standard thermodynamic parameters for encapsulation were determined for a series of protiated and fluorinated iridium guests in a variety of polar solvents using van't Hoff analysis. The encapsulation process for these guests exhibited enthalpy-entropy compensation effects. In solvents such as water and methanol, error analysis suggests a chemical origin for this behavior. In contrast, error analysis of this compensation behavior in polar aprotic solvents such as dimethyl sulfoxide reveals that this correlation is due to an artifact inherent in the intrinsic correlation between the enthalpy and entropy terms in the van't Hoff analysis. Guest encapsulation in polar protic solvents such as water appears to be driven by initial desolvation of the guest with concomitant rearrangement of the hydrogen bond networks in solution. This behavior shares common characteristics with other synthetic and natural host-guest and molecular recognition processes in aqueous solution, ranging from simple crown ether to complex enzyme-ligand interactions.
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Cápsulas/química , Entropía , Sustancias Macromoleculares/química , Compuestos Organometálicos/química , Termodinámica , Agua/química , Ligandos , Modelos Químicos , Solventes/química , TemperaturaRESUMEN
An alpha-diimine ligand (1) containing an axial donating pyridine group is developed for late metal polymerization catalysis. Despite having no substitution on the bottom face of the ligand, the nickel and palladium complexes of 1 are highly active for ethylene polymerization, producing linear high molecular weight polymers. For example, 1-NiBr2 (3) forms PE with a Mn of up to 109 224 g/mol with 1.4 branches/1000 C's. Similarly, 1-PdMeCl (5) forms PE with a Mn of up to 880 379 g/mol with 5.1 branches/1000 C's. In sharp contrast, catalysts containing the control ligand (2) consisting of a noncoordinating phenyl group gave only low molecular weight branched oligomers. It is observed that AlMe2Cl plays a specific role in generating the active species for the pyridine-based complexes. Presumably, the pyridine group may interact with AlMe2Cl to form a bimetallic species which suppresses the beta-hydride elimination process, hence resulting in reduced chain transfer and more linear structure.
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Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe and effective insulin sensitizers, absent of weight gain, has been a long-standing goal of diabetes research. G-protein coupled receptor 120 (GPR120) has recently emerged as a potential therapeutic target for treating T2DM. Natural occurring, and more recently, synthetic agonists have been associated with insulin sensitizing, anti-inflammatory, and fat metabolism effects. Herein we describe the design, synthesis, and evaluation of a novel spirocyclic GPR120 agonist series, which culminated in the discovery of potent and selective agonist 14. Furthermore, compound 14 was evaluated in vivo and demonstrated acute glucose lowering in an oral glucose tolerance test (oGTT), as well as improvements in homeostatic measurement assessment of insulin resistance (HOMA-IR; a surrogate marker for insulin sensitization) and an increase in glucose infusion rate (GIR) during a hyperinsulinemic euglycemic clamp in diet-induced obese (DIO) mice.
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BACKGROUND: We sought to determine the cost-effectiveness of different treatment strategies for patients with pulmonary metastases from soft tissue sarcoma. METHODS: We constructed a decision tree to model the outcomes of 4 treatment strategies for patients with pulmonary metastases from soft tissue sarcoma: pulmonary resection, systemic chemotherapy, pulmonary resection and systemic chemotherapy, and no treatment. Data from 1124 patients with pulmonary metastases from soft tissue sarcoma were used to estimate disease-specific survival for pulmonary resection and no treatment. Outcomes of systemic chemotherapy and pulmonary resection and of systemic chemotherapy were estimated by assuming a 12-month improvement in disease-specific survival with chemotherapy; this was done on the basis of the widely held but unproven assumption that chemotherapy provides a survival benefit in patients with metastatic soft tissue sarcoma. Direct costs were examined for a series of patients who underwent protocol-based pulmonary resection or doxorubicin/ifosfamide-based chemotherapy. RESULTS: The mean cost of pulmonary resection was 20,339 dollars per patient; the mean cost of 6 cycles of chemotherapy was 99,033 dollars. Compared with no treatment and assuming a 12-month survival advantage with chemotherapy, the incremental cost-effectiveness ratio was 14,357 dollars per life-year gained for pulmonary resection, 104,210 dollars per life-year gained for systemic chemotherapy, and 51,159 dollars per life-year gained for pulmonary resection and systemic chemotherapy. Compared with pulmonary resection, the incremental cost-effectiveness ratio of pulmonary resection and systemic chemotherapy was 108,036 dollars per life-year gained. Sensitivity analyses showed that certain patient and tumor features, as well as the assumed benefit of chemotherapy, affected cost-effectiveness. CONCLUSIONS: For patients with pulmonary metastases from soft tissue sarcoma who were surgical candidates, pulmonary resection was the most cost-effective treatment strategy evaluated. Even with favorable assumptions regarding its clinical benefit, systemic chemotherapy alone, compared with no treatment, was not a cost-effective treatment strategy for these patients.
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Antineoplásicos/economía , Neoplasias Pulmonares/economía , Neoplasias Pulmonares/secundario , Neumonectomía/economía , Sarcoma/economía , Sarcoma/secundario , Antineoplásicos/uso terapéutico , Terapia Combinada , Análisis Costo-Beneficio , Costos y Análisis de Costo , Técnicas de Apoyo para la Decisión , Árboles de Decisión , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/terapia , Sarcoma/mortalidad , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Drug discovery and development is a challenging area. During the drug optimization process, available drug compounds often have poor physicochemical and biopharmaceutical properties, making the proper in vivo evaluation of these compounds difficult. To address these challenges, drug nanoparticles of poorly soluble compounds have emerged as a promising formulation approach. Herein, we report on a new drug sparing technology utilizing low shear acoustic mixing to rapidly identify optimized nanosuspension formulations for a wide range of compounds with dramatically improved material and time efficiencies. This approach has several key advantages over typical methods of preparing nanoparticles, including miniaturization of the milling process, the ability to evaluate multiple formulation conditions in a high throughput manner, and direct translation to optimized formulation scale-up for in vivo studies. Furthermore, there are additional benefits obtained with this new approach resulting in nanosuspension formulations with significant stability and physical property enhancements over those obtained using traditional media milling techniques. These advantages make this approach highly suitable for the rapid evaluation of potential drug candidates in the discovery and development space.