RESUMO
PURPOSE: Whey protein isolate (WPI) has previously been shown to be a promising new excipient for the development of amorphous solid dispersions (ASD) at a high drug loading of 50% (w/w). Whilst WPI is a protein mixture, comprising mainly the three proteins ß-lactoglobulin (BLG), α-lactalbumin (ALA), casein glycomacropeptides (CGMP), the individual contributions of these three proteins to the overall performance of whey protein based ASDs has still not been investigated. In addition, the limitations of the technology at even higher drug loadings (i.e., more than 50%) have not yet been explored. In this study, BLG, ALA, CGMP and WPI were each prepared as ASDs with the two poorly water-soluble drugs (Compound A and Compound B) at 50%, 60% and 70% drug loadings. METHODS: Solid state characterization, dissolution rate and physical stability of the obtained samples were analyzed. RESULTS: All the obtained samples were amorphous and showed faster dissolution rates compared to the respective pure crystalline drugs. However, the BLG based formulations-at least for Compound A-were outperforming the other ASDs in terms of stability, dissolution enhancement and solubility increase. CONCLUSION: Overall, the study confirmed that the investigated whey proteins showed their potential in developing ASDs even at high drug loadings of up to 70%.
Assuntos
Liberação Controlada de Fármacos , Proteínas do Soro do Leite , Cristalização , SolubilidadeRESUMO
Microbial adhesion to host cells represents the initial step in the infection process. Several methods have been explored to inhibit microbial adhesion including the use of glycopolymers based on mannose, galactose, sialic acid and glucose. These sugar receptors are, however, abundant in the body, and are not unique to bacteria. Trehalose, in contrast, is a unique disaccharide that is widely expressed by microbes. This carbohydrate has not yet been explored as an anti-adhesive agent. Herein, gold nanoparticles (AuNPs) coated with trehalose-based polymers were prepared and compared to glucose-functionalized AuNPs and examined for their ability to prevent binding to endothelial cells. Acting as anti-adhesive agents, trehalose-functionalized NPs decreased the binding of S.â aureus to HUVECs, while outperforming the control NPs. Microscopy revealed that trehalose-coated NPs bound strongly to S.â aureus compared to the controls. In conclusion, nanoparticles based on trehalose could be a non-toxic alternative to inhibit S.â aureus infection.
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Antibacterianos/farmacologia , Glucose/química , Ouro/química , Nanopartículas Metálicas/química , Staphylococcus aureus/efeitos dos fármacos , Trealose/química , Antibacterianos/síntese química , Antibacterianos/química , Aderência Bacteriana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Staphylococcus aureus/fisiologiaRESUMO
Crystallization in the presence of additives such as surfactants, polymers or impurities has been widely investigated in the pharmaceutical and chemical industries in order to change the crystal habit or to obtain a more desirable polymorph, affect crystal growth and influence dissolution. However, in this study, we investigated the concept of crystallization in the presence of surfactants in order to incorporate into the crystal lattice, a small amount (less than 1% w/w) of surfactant, sodium lauryl sulfate (SLS). The resulting crystals were further compared to crystals coated with SLS using a washing procedure; in order to assess whether either procedure generates improvements in the apparent solubility and dissolution of a poorly soluble drug so it can be filled directly into a capsule without the need of a complex formulation process.
Assuntos
Composição de Medicamentos , Cápsulas , Cristalização , Dodecilsulfato de Sódio , Solubilidade , TensoativosRESUMO
Subcutaneous (SC) drug delivery can be a safe, effective alternative to the traditional intravenous route of administration, potentially offering notable advantages for both patients and healthcare providers. The SC Drug Development & Delivery Consortium convened in 2018 to raise awareness of industry challenges to advance the development of patient-centric SC drug delivery strategies. The SC Consortium identified better understanding of patient preferences and perspectives as necessary to optimize SC product design attributes and help guide design decisions during SC product development. This manuscript provides a comprehensive overview of patient-centric factors for consideration in the SC drug delivery design and development process with the aim of establishing a foundation of existing knowledge for patient experiences related to SC drug delivery. This overview is informed by the outcomes of a multi-step survey of Consortium members and key pharmaceutical stakeholders. Framed in the context of the patient's treatment journey, the survey findings offer future perspectives to fill data gaps to advance patient-centric SC drug delivery.
Assuntos
Sistemas de Liberação de Medicamentos , Indústria Farmacêutica , Humanos , Injeções Subcutâneas , Preferência do Paciente , Desenho de Fármacos , Adesão à MedicaçãoRESUMO
The way a drug molecule is administered has always had a profound impact on people requiring medical interventions - from vaccine development to cancer therapeutics. In the Controlled Release Society Fall Symposium 2022, a trans-institutional group of scientists from industry, academia, and non-governmental organizations discussed what a breakthrough in the field of drug delivery constitutes. On the basis of these discussions, we classified drug delivery breakthrough technologies into three categories. In category 1, drug delivery systems enable treatment for new molecular entities per se, for instance by overcoming biological barriers. In category 2, drug delivery systems optimize efficacy and/or safety of an existing drug, for instance by directing distribution to their target tissue, by replacing toxic excipients, or by changing the dosing reqimen. In category 3, drug delivery systems improve global access by fostering use in low-resource settings, for instance by facilitating drug administration outside of a controlled health care institutional setting. We recognize that certain breakthroughs can be classified in more than one category. It was concluded that in order to create a true breakthrough technology, multidisciplinary collaboration is mandated to move from pure technical inventions to true innovations addressing key current and emerging unmet health care needs.
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Sistemas de Liberação de Medicamentos , Neoplasias , Humanos , Preparações Farmacêuticas , TecnologiaRESUMO
LY2457546 is a potent and orally bioavailable inhibitor of multiple receptor tyrosine kinases involved in angiogenic and tumorigenic signalling. In biochemical and cellular assays, LY2457546 demonstrates potent activity against targets that include VEGFR2 (KDR), PDGFRß, FLT-3, Tie-2 and members of the Eph family of receptors. With activities against both Tie2 and Eph receptors, LY2457546 possesses an activity profile that distinguishes it from multikinase inhibitors. When compared head to head with sunitinib, LY2457546 was more potent for inhibition of endothelial tube formation in an in vitro angiogenesis co-culture model with an intermittent treatment design. In vivo, LY2457546 inhibited VEGF-driven autophosphorylation of lung KDR in the mouse and rat in a dose and concentration dependent manner. LY2457546 was well tolerated and exhibited efficacy in a 13762 syngeneic rat mammary tumor model in both once and twice daily continuous dosing schedules and in mouse human tumor xenograft models of lung, colon, and prostate origin. Additionally, LY2457546 caused complete regression of well-established tumors in an acute myelogenous leukemia (AML) FLT3-ITD mutant xenograft tumor model. The observed efficacy that was displayed by LY2457546 in the AML FLT3-ITD mutant tumor model was superior to sunitinib when both were evaluated using equivalent doses normalized to in vivo inhibition of pKDR in mouse lung. LY2457546 was well tolerated in non-clinical toxicology studies conducted in rats and dogs. The majority of the toxicities observed were similar to those observed with other multi-targeted anti-angiogenic kinase inhibitors (MAKs) and included bone marrow hypocellularity, hair and skin depigmentation, cartilage dysplasia and lymphoid organ degeneration and necrosis. Thus, the unique spectrum of target activity, potent in vivo anti-tumor efficacy in a variety of rodent and human solid tumor models, exquisite potency against a clinically relevant model of AML, and non-clinical safety profile justify the advancement of LY2457546 into clinical testing.
Assuntos
Acetanilidas/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Acetanilidas/síntese química , Acetanilidas/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/farmacologia , Animais , Células CHO , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Cães , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Nus , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
PURPOSE: To examine the precipitation and supersaturation behavior of ten weak bases in terms of the relationship between pH-concentration-time profiles and the solid state properties of the precipitated material. METHODS: Initially the compound was dissolved at low pH, followed by titration with base to induce precipitation. Upon precipitation, small aliquots of acid or base were added to induce slight subsaturation and supersaturation respectively and the resultant pH gradient was determined. The concentration of the unionized species was calculated as a function of time and pH using mass and charge balance equations. RESULTS: Two patterns of behavior were observed in terms of the extent and duration of supersaturation arising following an increase in pH and this behavior could be rationalized based on the crystallization tendency of the compound. For compounds that did not readily crystallize, an amorphous precipitate was formed and a prolonged duration of supersaturation was observed. For compounds that precipitated to crystalline forms, the observed supersaturation was short-lived. CONCLUSION: This study showed that supersaturation behavior has significant correlation with the solid-state properties of the precipitate and that pH-metric titration methods can be utilized to evaluate the supersaturation behavior.
Assuntos
Álcalis/química , Soluções/química , Ácidos/química , Precipitação Química , Cristalização , Concentração de Íons de Hidrogênio , Potenciometria , SolubilidadeRESUMO
INTRODUCTION: We see a development in the field of long-acting products to serve patients with chronic diseases by providing benefits in adherence, efficacy, and safety of the treatment. This review investigates features of long-acting products on the market/pipeline to understand which drug substance (DS) and drug product (DP) characteristics likely enable a successful patient-centric, low-dosing frequency product. AREAS COVERED: This review evaluates marketed/pipeline long-acting products with greater than 1 week release of small molecules and peptides by oral and injectable route of administration (RoA), with particular focus on patient centricity, adherence impact, health outcomes, market trends, and the match of DS/DP technologies which lead to market success. EXPERT OPINION: Emerging trends are expected to change the field of long-acting products in the upcoming years by increasing capability in engineered molecules (low solubility, long half-life, high potency, etc.), directly developing DP as long-acting oral/injectable, increasing the proportion of products for local drug delivery, and a direction toward more subcutaneous, self-administered products. Among long-acting injectable products, nanosuspensions show a superiority in dose per administration and dosing interval, overwhelming the field of infectious diseases with the recently marketed products.
Assuntos
Sistemas de Liberação de Medicamentos , Assistência Centrada no Paciente , Humanos , Injeções , Solubilidade , Preparações de Ação RetardadaRESUMO
Poorly water-soluble drugs pose a significant challenge to developability due to poor oral absorption leading to poor bioavailability. Several approaches exist that improve the oral absorption of such compounds by enhancing the aqueous solubility and/or dissolution rate of the drug. These include chemical modifications such as salts, co-crystals or prodrugs and physical modifications such as complexation, nanocrystals or conversion to amorphous form. Among these formulation strategies, the conversion to amorphous form has been successfully deployed across the pharmaceutical industry, accounting for approximately 30% of the marketed products that require solubility enhancement and making it the most frequently used technology from 2000 to 2020. This article discusses the underlying scientific theory and influence of the active compound, the material properties and manufacturing processes on the selection and design of amorphous solid dispersion (ASD) products as marketed products. Recent advances in the analytical tools to characterize ASDs stability and ability to be processed into suitable, patient-centric dosage forms are also described. The unmet need and regulatory path for the development of novel ASD polymers is finally discussed, including a description of the experimental data that can be used to establish if a new polymer offers sufficient differentiation from the established polymers to warrant advancement.
RESUMO
BACKGROUND: Olanzapine long-acting injection (LAI) is a salt-based depot antipsychotic combining olanzapine and pamoic acid. The slow intramuscular dissolution of this practically insoluble salt produces an extended release of olanzapine lasting up to 4 weeks. However, in a small number of injections (< 0.1%), patients experienced symptoms suggestive of olanzapine overdose, a phenomenon that has been termed "post-injection delirium/sedation syndrome" (PDSS). The authors conducted a series of parallel investigations into the possible reasons PDSS events occur. METHODS: Healthcare providers involved in the PDSS cases were queried for clinical information around the events. Plasma samples from patients experiencing PDSS were collected when possible (12/30 cases) and olanzapine concentrations compared with the known pharmacokinetic profile for olanzapine LAI. Product batches and used vials from the PDSS cases were evaluated for compliance with established manufacturing standards and/or possible user error. Because this depot formulation depends upon slow dissolution at the intramuscular injection site, in-vitro experiments were conducted to assess solubility of olanzapine pamoate in various media. RESULTS: Injection administrators reported no unusual occurrences during the injection. No anomalies were found with the product batches or the remaining suspension in the used vials. Olanzapine concentrations during PDSS events were higher than the expected 5-73 ng/mL range, with concentrations exceeding 100 ng/mL and in some cases reaching >600 ng/mL during the first hours after injection but then returning to the expected therapeutic range within 24 to 72 hours. Solubility and dissolution rate of olanzapine pamoate were also found to be substantially greater in plasma than in other media such as those approximating the environment in muscle tissue. CONCLUSIONS: Manufacturing irregularities, improper drug reconstitution, and inappropriate dosing were ruled out as possible causes of PDSS. In-vitro solubility and in-vivo pharmacokinetic investigations suggest that PDSS is related to exposure of the injected product to a substantial volume of blood. This exposure is most likely the result of unintended partial intravascular injection or blood vessel injury during the injection (occurring even with proper injection technique) with subsequent seepage of the medication into the vasculature, which would produce higher than intended olanzapine concentrations and symptoms consistent with PDSS. TRIAL REGISTRATION: ClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.
Assuntos
Antipsicóticos/efeitos adversos , Benzodiazepinas/efeitos adversos , Esquizofrenia/tratamento farmacológico , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Benzodiazepinas/administração & dosagem , Benzodiazepinas/farmacocinética , Ensaios Clínicos como Assunto/estatística & dados numéricos , Preparações de Ação Retardada , Overdose de Drogas/etiologia , Overdose de Drogas/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Humanos , Injeções Intramusculares , Olanzapina , Síndrome , Resultado do TratamentoRESUMO
Subcutaneous (SC) delivery of biotherapeutics is well established as a route of administration across many therapeutic areas and has been shown to be effective and well-tolerated. It can offer several advantages over intravenous administration. This notwithstanding, there remain critical development issues and knowledge gaps in SC drug delivery. To articulate and address these issues, the SC Drug Delivery and Development Consortium was convened in 2018 as a pre-competitive collaboration of industry experts in drug delivery, device development, and commercialization. In this review, we outline the Consortium's vision and mission in advancing the development of patient-centered biotherapeutics and establishing a collaborative organization that facilitates open sharing of information and gives voice to diverse viewpoints from SC experts across industries and disciplines. Additionally, we describe the current landscape and challenges associated with SC administration of therapeutic proteins (specifically monoclonal antibodies) and offer insights into potential solutions to these challenges within the context of 8 problem statements developed by the Consortium to highlight key gaps, unmet needs, and actionable issues. Current and future opportunities to accelerate progress in the field through technological advances and the development of drug delivery tools are also discussed.
Assuntos
Sistemas de Liberação de Medicamentos , Tela Subcutânea , Administração Intravenosa , Anticorpos Monoclonais , Humanos , Injeções SubcutâneasRESUMO
Despite the increasing trend towards subcutaneous delivery of monoclonal antibodies, factors influencing the subcutaneous bioavailability of these molecules remain poorly understood. To address critical knowledge gaps and issues during development of subcutaneous dosage forms for monoclonal antibodies, the Subcutaneous Drug Delivery and Development Consortium was convened in 2018 as a pre-competitive collaboration of recognized industry experts. One of the Consortium's eight problem statements highlights the challenges of predicting human bioavailability of subcutaneously administered monoclonal antibodies due to a lack of reliable in vitro and preclinical in vivo predictive models. In this paper, we assess the current landscape in subcutaneous bioavailability prediction for monoclonal antibodies and discuss the gaps and opportunities associated with bioavailability models for biotherapeutics. We also issue an open challenge to industry and academia, encouraging the development of reliable models to enable subcutaneous bioavailability prediction of therapeutic large molecules in humans and improve translation from preclinical species.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Produtos Biológicos/administração & dosagem , Produtos Biológicos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Anticorpos Monoclonais/química , Área Sob a Curva , Disponibilidade Biológica , Produtos Biológicos/química , Relação Dose-Resposta a Droga , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Injeções Subcutâneas , Modelos Biológicos , SolubilidadeRESUMO
The druggability and developability space is rapidly evolving in the post-genomic era. In the past, Lipinski's rule-of-five (Ro5) emerged and served as a guide for drug-like molecule design for oral delivery in the traditional druggable target space. In contrast, in this new era, a transition is occurring in drug discovery towards novel approaches to bind and modulate challenging biological targets that have led to transformative treatments for patients. Consequently, drugging novel targets using a variety of emerging molecular modalities, namely beyond the Ro5 (bRo5) small molecules (such as protein-protein interaction modulators, protein-targeted chimeras, or PROTACs), peptide/peptidomimetics, and nucleic acid-based modalities, have become a key focus in drug discovery. Herein, the emerging druggability and developability space is discussed side by side to build a general understanding of the potential development challenges of these novel modalities. An overview is provided on the evolving novel targets and molecular modalities, followed by a detailed analysis of the druggability aspects as well as the strategies used to progress drug candidate, and the trending chemistry and formulation strategies used to assess developability.
Assuntos
Desenvolvimento de Medicamentos , Descoberta de Drogas , Terapia de Alvo Molecular , Preparações Farmacêuticas/química , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Estrutura Molecular , Mapas de Interação de Proteínas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Advances in understanding of human disease have prompted the U.S. Food and Drug Administration to classify certain molecules as "break-through therapies," providing an accelerated review that may potentially enhance the quality of patient lives. With this designation come compressed timelines to develop drug products, which are not only suitable for clinic trials but can also be approved and brought to the market rapidly. Early risk identification for decreased oral absorption due to drug-drug interactions with proton pump inhibitors (PPIs) or acid-reducing agents (ARAs) is paramount to an effective drug product development strategy. An early ARA/PPI drug-drug interaction (DDI) risk identification strategy has been developed using physiologically based absorption modeling that readily integrates ADMET predictor generated in silico estimates or measured in vitro solubility, permeability, and ionization constants. Observed or predicted pH-solubility profile data along with pKas and drug dosing parameters were used to calculate a fraction of drug absorbed ratio in absence and presence of ARAs/PPIs. An integrated physiologically based pharmacokinetic absorption model using GastroPlus™ with pKa values fitted to measured pH-solubility profile data along with measured permeability data correctly identified the observed ARA/PPI DDI for 78% (16/22) of the clinical studies. Formulation strategies for compounds with an anticipated pH-mediated DDI risk are presented.
Assuntos
Interações Medicamentosas/fisiologia , Preparações Farmacêuticas/metabolismo , Inibidores da Bomba de Prótons/química , Inibidores da Bomba de Prótons/metabolismo , Absorção Fisiológica/efeitos dos fármacos , Administração Oral , Simulação por Computador , Descoberta de Drogas/métodos , Humanos , Modelos Biológicos , Permeabilidade/efeitos dos fármacos , Solubilidade/efeitos dos fármacosRESUMO
The Wnt pathway has been shown to regulate bone homeostasis and to influence some bone disease states. We utilized a zebrafish model system to study the effects of a synthetic, orally bioavailable glycogen synthase kinase-3ß (GSK3ß) inhibitor LSN 2105786, which activates Wnt signaling during bone healing and embryogenesis. GSK3ß inhibitor treatment was used to phenocopy GSK3ß morpholino oligonucleotide (MO) knockdown in zebrafish embryos. Human and zebrafish synthetic mRNA injection were similarly effective at rescue of GSK3ß MO knockdown. During caudal fin regeneration, bony rays are the first structure to differentiate in zebrafish fins, providing a useful model to study bone healing. Caudal fin regeneration experiments were conducted using various concentrations of a GSK3ß inhibitor, examining duration and concentration dependence on regenerative outgrowth. Experiments revealed continuous low concentration (4-5 nM) treatment to be more effective at increasing regeneration than intermittent dosing. Higher concentrations inhibited fin growth, perhaps by excessive stimulation of differentiation programs. Increased Wnt responsive gene expression and differentiation were observed in response to GSK3b inhibitor treatment. Activating Wnt signaling also increased cell proliferation and osteoblast differentiation in fin regenerates. Together, these data indicate that bone healing in zebrafish fin regeneration was improved by activating Wnt signaling using GSK3b inhibitor treatment. In addition, caudal fin regeneration is useful to evaluate dose-dependent pharmacological efficacy in bone healing, various dosing regimens and possible toxicological effects of compounds.
RESUMO
Studies have shown that nanoparticles (NPs) are cleared through the mononuclear phagocyte system (MPS). Pharmacokinetic studies of Doxil, DaunoXome, micellar doxorubicin (SP1049C) and small molecule (SM) doxorubicin were performed in SCID mice, Sprague-Dawley rats, and beagle dogs. An ex vivo MPS profiling platform was used to evaluate the interaction between the same agents, as well as colloid-forming and non-colloid forming SM drugs. In all species, the systemic clearance was highest for SP1049C and lowest for Doxil. With the exception of dog blood, the MPS screening results of mouse and rat blood showed that the greatest reduction in phagocytosis occurred after the ex vivo addition of SM-doxorubicin>SP1049C>DaunoXome>Doxil. The MPS profiling platform in rats, but not dogs, could differentiate between colloid forming and non-colloid forming drugs. The results of the MPS profiling platform were generally consistent with in vivo clearance rates of NP and SM anticancer drugs in mice and rats. This study suggests the MPS profiling platform is an effective method to screen and differentiate the important characteristics of NPs and colloid-forming drugs that affect their in vivo clearance. Implications of these findings on preclinical prediction of human clearance are discussed.
Assuntos
Coloides/farmacologia , Sistema Fagocitário Mononuclear/efeitos dos fármacos , Nanopartículas/química , Animais , Cães , Humanos , Camundongos , Camundongos SCID , Ratos , Ratos Sprague-DawleyRESUMO
Nitazoxanide (NTZ) and its metabolite tizoxanide (TIZ) were studied as antimycobacterial agents in vitro (in mycobacterial growth indicator tube [MGIT] cultures) and in a whole blood bactericidal assay. Both NTZ and TIZ show high protein binding. In MGIT cultures (albumin concentration = 78 µM), inhibition of Mycobacterium tuberculosis growth occurred at total drug concentrations of ≥16 µg/ml, whereas in whole blood cultures (albumin concentration = 350 µM), ≥128 µg/ml was required. Free drug fractions at these two conditions were estimated to be 69% and 2%, respectively. Co-incubation of NTZ and TIZ in human plasma for 72 h nearly completely eliminated their ability to inhibit mycobacterial growth in MGIT. Interactions with plasma proteins may limit the potential of NTZ and TIZ as drugs for human tuberculosis.
Assuntos
Antituberculosos/farmacologia , Hemocultura , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazóis/farmacologia , Antituberculosos/sangue , Relação Dose-Resposta a Droga , Humanos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/patogenicidade , Nitrocompostos , Ligação Proteica , Albumina Sérica/metabolismo , Albumina Sérica Humana , Teste Bactericida do Soro , Tiazóis/sangue , Fatores de TempoRESUMO
The PI3K/AKT/mTOR pathway is among the most frequently altered pathways in cancer cell growth and survival. LY3023414 is a complex fused imidazoquinolinone with high solubility across a wide pH range designed to inhibit class I PI3K isoforms and mTOR kinase. Here, we describe the in vitro and in vivo activity of LY3023414. LY3023414 was highly soluble at pH 2-7. In biochemical testing against approximately 266 kinases, LY3023414 potently and selectively inhibited class I PI3K isoforms, mTORC1/2, and DNA-PK at low nanomolar concentrations. In vitro, inhibition of PI3K/AKT/mTOR signaling by LY3023414 caused G1 cell-cycle arrest and resulted in broad antiproliferative activity in cancer cell panel screens. In vivo, LY3023414 demonstrated high bioavailability and dose-dependent dephosphorylation of PI3K/AKT/mTOR pathway downstream substrates such as AKT, S6K, S6RP, and 4E-BP1 for 4 to 6 hours, reflecting the drug's half-life of 2 hours. Of note, equivalent total daily doses of LY3023414 given either once daily or twice daily inhibited tumor growth to similar extents in multiple xenograft models, indicating that intermittent target inhibition is sufficient for antitumor activity. In combination with standard-of-care drugs, LY3023414 demonstrated additive antitumor activity. The novel, orally bioavailable PI3K/mTOR inhibitor LY3023414 is highly soluble and exhibits potent in vivo efficacy via intermittent target inhibition. It is currently being evaluated in phase I and II trials for the treatment of human malignancies. Mol Cancer Ther; 15(10); 2344-56. ©2016 AACR.
Assuntos
Antineoplásicos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Modelos Moleculares , Conformação Molecular , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Ligação Proteica , Inibidores de Proteínas Quinases/química , Transdução de Sinais/efeitos dos fármacos , Solubilidade , Serina-Treonina Quinases TOR/química , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This summary workshop report highlights presentations and over-arching themes from an October 2011 workshop. Discussions focused on best practices in the application of biopharmaceutics in oral drug product development and evolving bioequivalence approaches. Best practices leverage biopharmaceutic data and other drug, formulation, and patient/disease data to identify drug development challenges in yielding a successfully performing product. Quality by design and product developability paradigms were discussed. Development tools include early development strategies to identify critical absorption factors and oral absorption modeling. An ongoing theme was the desire to comprehensively and systematically assess risk of product failure via the quality target product profile and root cause and risk analysis. However, a parallel need is reduced timelines and fewer resources. Several presentations discussed applying Biopharmaceutics Classification System (BCS) and in vitro-in vivo correlations in development and in post-development and discussed both resource savings and best scientific practices. The workshop also focused on evolving bioequivalence approaches, with emphasis on highly variable products (HVDP), as well as specialized modified-release products. In USA, two bioequivalence approaches for HVDP are the reference-scaled average bioequivalence approach and the two-stage group-sequential design. An adaptive sequential design approach is also acceptable in Canada. In European Union, two approaches for HVDP are a two-stage design and an approach to widen C (max) acceptance limits. For some specialized modified-release products, FDA now requests partial area under the curve. Rationale and limitations of such metrics were discussed (e.g., zolpidem and methylphenidate). A common theme was the benefit of the scientific and regulatory community developing, validating, and harmonizing newer bioequivalence methodologies (e.g., BCS-based waivers and HVDP trial designs).