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Thrombocytopenia, hemorrhage, anemia, and infection are life-threatening issues following accidental or intentional radiation exposure. Since few therapeutics are available, safe and efficacious small molecules to mitigate radiation-induced injury need to be developed. Our previous study showed the synthetic TLR2/TLR6 ligand fibroblast stimulating lipopeptide (FSL-1) prolonged survival and provided MyD88-dependent mitigation of hematopoietic acute radiation syndrome (H-ARS) in mice. Although mice and humans differ in TLR number, expression, and function, nonhuman primate (NHP) TLRs are like those of humans; therefore, studying both animal models is critical for drug development. The objectives of this study were to determine the efficacy of FSL-1 on hematopoietic recovery in small and large animal models subjected to sublethal total body irradiation and investigate its mechanism of action. In mice, we demonstrate a lack of adverse effects, an easy route of delivery (subcutaneous) and efficacy in promoting hematopoietic progenitor cell proliferation by FSL-1. NHP given radiation, followed a day later with a single subcutaneous administration of FSL-1, displayed no adversity but showed elevated hematopoietic cells. Our analyses revealed that FSL-1 promoted red blood cell development and induced soluble effectors following radiation exposure. Cytologic analysis of bone marrow aspirates revealed a striking enhancement of mononuclear progenitor cells in FSL-1-treated NHP. Combining the efficacy of FSL-1 in promoting hematopoietic cell recovery with the lack of adverse effects induced by a single administration supports the application of FSL-1 as a viable countermeasure against H-ARS.
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Síndrome Aguda da Radiação , Receptor 2 Toll-Like , Humanos , Camundongos , Animais , Receptor 6 Toll-Like , Ligantes , Síndrome Aguda da Radiação/tratamento farmacológico , Primatas , FibroblastosRESUMO
An objective of the Precision Medicine Initiative, launched in 2015 by the US Food and Drug Administration and National Institutes of Health, is to optimize and individualize dosing of drugs, especially anticancer agents, with high pharmacokinetic and pharmacodynamic variability. The American Society of Clinical Oncology recently reported that 40% of obese patients receive insufficient chemotherapy doses and exposures, which may lead to reduced efficacy, and recommended pharmacokinetic studies to guide appropriate dosing in these patients. These issues will only increase in importance as the incidence of obesity in the population increases. This publication reviews the effects of obesity on (1) tumor biology, development of cancer, and antitumor response; (2) pharmacokinetics and pharmacodynamics of small-molecule anticancer drugs; and (3) pharmacokinetics and pharmacodynamics of complex anticancer drugs, such as carrier-mediated agents and biologics. These topics are not only important from a scientific research perspective but also from a drug development and regulator perspective. Thus, it is important to evaluate the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents in all categories of body habitus and especially in patients who are obese and morbidly obese. As the effects of obesity on the pharmacokinetics and pharmacodynamics of anticancer agents may be highly variable across drug types, the optimal dosing metric and algorithm for difference classes of drugs may be widely different. Thus, studies are needed to evaluate current and novel metrics and methods for measuring body habitus as related to optimizing the dose and reducing pharmacokinetic and pharmacodynamic variability of anticancer agents in patients who are obese and morbidly obese.
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Antineoplásicos , Neoplasias , Obesidade Mórbida , Humanos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacocinética , Preparações Farmacêuticas , Neoplasias/tratamento farmacológico , Desenvolvimento de Medicamentos , FarmacocinéticaRESUMO
This article reports on an American Society of Pharmacology and Therapeutics, Division of Drug Metabolism and Disposition symposium held at Experimental Biology on April 2, 2022, in Philadelphia. As of July 2022, over 500 million people have been infected with SARS-CoV-2 (the virus causing COVID-19) and over 12 billion vaccine doses have been administered. Clinically significant interactions between viral infections and hepatic drug metabolism were first recognized over 40 years ago during a cluster of pediatric theophylline toxicity cases attributed to reduced hepatic drug metabolism amid an influenza B outbreak. Today, a substantive body of research supports that the activated innate immune response generally decreases hepatic cytochrome P450 activity. The interactions extend to drug transporters and other organs and have the potential to impact drug absorption, distribution, metabolism, and excretion (ADME). Based on this knowledge, altered ADME is predicted with SARS-CoV-2 infection or vaccination. The report begins with a clinical case exploring the possibility of SARS-CoV-2 vaccination increasing clozapine levels. This is followed by discussions of how SARS-CoV-2 infection or vaccines alter the metabolism and disposition of complex drugs, such as nanoparticles and biologics and small molecule therapies. The review concludes with a discussion of the effects of viral infections on placental amino acid transport and their potential to impact fetal development. The session improved our understanding of the impact of emerging viral infections and vaccine technologies on drug metabolism and disposition, which will help mitigate drug toxicity and improve drug and vaccine safety and effectiveness. SIGNIFICANCE STATEMENT: Altered pharmacokinetics of small molecule and complex molecule drugs and fetal brain distribution of amino acids following SARS-CoV-2 infection or immunization are possible. The proposed mechanisms involve decreased liver cytochrome P450 metabolism of small molecules, enhanced innate immune system metabolism of complex molecules, and altered placental and fetal blood-brain barrier amino acid transport, respectively. Future research is needed to understand the effects of these interactions on adverse drug responses, drug and vaccine safety, and effectiveness and fetal neurodevelopment.
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Vacinas contra COVID-19 , COVID-19 , Criança , Feminino , Humanos , Gravidez , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Placenta , SARS-CoV-2 , VacinasRESUMO
Standard small molecule and nanoparticulate chemotherapies are used for cancer treatment; however, their effectiveness remains highly variable. One reason for this variable response is hypothesized to be due to nonspecific drug distribution and heterogeneity of the tumor microenvironment, which affect tumor delivery of the agents. Nanoparticle drugs have many theoretical advantages, but due to variability in tumor microenvironment (TME) factors, the overall drug delivery to tumors and associated antitumor response are low. The nanotechnology field would greatly benefit from a thorough analysis of the TME factors that create these physiological barriers to tumor delivery and treatment in preclinical models and in patients. Thus, there is a need to develop methods that can be used to reveal the content of the TME, determine how these TME factors affect drug delivery, and modulate TME factors to increase the tumor delivery and efficacy of nanoparticles. In this review, we will discuss TME factors involved in drug delivery, and how biomedical imaging tools can be used to evaluate tumor barriers and predict drug delivery to tumors and antitumor response.
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BACKGROUND: Minibeam radiation therapy is an experimental radiation therapy utilizing an array of parallel submillimeter planar X-ray beams. In preclinical studies, minibeam radiation therapy has been shown to eradicate tumors and cause significantly less damage to normal tissue compared to equivalent radiation doses delivered by conventional broadbeam radiation therapy, where radiation dose is uniformly distributed. METHODS: Expanding on prior studies that suggested minibeam radiation therapy increased perfusion in tumors, we compared a single fraction of minibeam radiation therapy (peak dose:valley dose of 28 Gy:2.1 Gy and 100 Gy:7.5 Gy) and broadbeam radiation therapy (7 Gy) in their ability to enhance tumor delivery of PEGylated liposomal doxorubicin and alter the tumor microenvironment in a murine tumor model. Plasma and tumor pharmacokinetic studies of PEGylated liposomal doxorubicin and tumor microenvironment profiling were performed in a genetically engineered mouse model of claudin-low triple-negative breast cancer (T11). RESULTS: Minibeam radiation therapy (28 Gy) and broadbeam radiation therapy (7 Gy) increased PEGylated liposomal doxorubicin tumor delivery by 7.1-fold and 2.7-fold, respectively, compared to PEGylated liposomal doxorubicin alone, without altering the plasma disposition. The enhanced tumor delivery of PEGylated liposomal doxorubicin by minibeam radiation therapy is consistent after repeated dosing, is associated with changes in tumor macrophages but not collagen or angiogenesis, and nontoxic to local tissues. Our study indicated that the minibeam radiation therapy's ability to enhance the drug delivery decreases from 28 to 100 Gy peak dose. DISCUSSION: Our studies suggest that low-dose minibeam radiation therapy is a safe and effective method to significantly enhance the tumor delivery of nanoparticle agents.
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Antibody-drug conjugates (ADCs) appear to be in a developmental boom, with five FDA approvals in the last two years and a projected market value of over $4 billion by 2024. Major advancements in the engineering of these novel cytotoxic drug carriers have provided a few early success stories. Although the use of these immunoconjugate agents are still in their infancy, valuable lessons in the engineering of these agents have been learned from both preclinical and clinical failures. It is essential to appreciate how the various mechanisms used to engineer changes in ADCs can alter the complex pharmacology of these agents and allow the ADCs to navigate the modern-day therapeutic challenges within oncology. This review provides a global overview of ADC characteristics which can be engineered to alter the interaction with the immune system, pharmacokinetic and pharmacodynamic profiles, and therapeutic index of ADCs. In addition, this review will highlight some of the engineering approaches being explored in the creation of the next generation of ADCs.
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Background This was a phase I/IIa study to investigate the tolerability, efficacy and pharmacokinetics (PK)/ pharmacodynamics (PD) of CRLX301, CDP-based nanoparticle formulation of docetaxel. Methods The study was conducted in two parts. In part 1, dose-escalation using a standard 3 + 3 design was performed in two dosing schedules (every week (QW) and every 3 weeks (Q3W)). Part 2 was comprised of a dose expansion at 75 mg/m2 Q3W. PK studies were performed on both dosing schedules. Results Forty-two patients were recruited onto the study with a median age of 64(range 38-76); median number of prior systemic therapies was 5(range 0-10). Grade 3/4 treatment-related toxicities included: neutropenia (21.4 %), infusion related reaction (11.9 %), anemia (7.1 %), fatigue (4.8 %), diarrhea (4.8 %), and peripheral neuropathy (4.8 %). The maximum tolerated dose was 75 mg/m2 given on the Q3W schedule and was not determined on the QW schedule. In this heavily pre-treated population, four patients (12.9 %) achieved stable disease (SD) ≥ 4 months and 2 patients (6.5 %) achieved partial response (PR) for a clinical benefit rate (CBR) of 19.4 % (6/31 patients). The PRs were seen in prostate and breast adenocarcinoma (one each). CRLX301 exhibited some PK advantages over docetaxel including higher retention of drug in plasma, slower clearance and controlled slow release of docetaxel from the carrier. Conclusions In this heavily pretreated patient population, the safety profile was acceptable for CRLX301 therapy. There was some evidence of preliminary tumor efficacy, but further work is necessary to find the optimal dose and schedule of this formulation.Clinicaltrials.gov trial registration number: NCT02380677 (Date of registration: March 2, 2015).
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Antineoplásicos/administração & dosagem , Docetaxel/administração & dosagem , Nanopartículas , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Preparações de Ação Retardada , Docetaxel/efeitos adversos , Docetaxel/farmacocinética , Relação Dose-Resposta a Droga , Liberação Controlada de Fármacos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Resultado do TratamentoRESUMO
Major developments in nanomedicines, such as nanoparticles (NPs), nanosomes, and conjugates, have revolutionized drug delivery capabilities over the past four decades. Although nanocarrier agents provide numerous advantages (e.g., greater solubility and duration of systemic exposure) compared to their small-molecule counterparts, there is considerable inter-patient variability seen in the systemic disposition, tumor delivery and overall pharmacological effects (i.e., anti-tumor efficacy and unwanted toxicity) of NP agents. This review aims to provide a summary of fundamental factors that affect the disposition of NPs in the treatment of cancer and why they should be evaluated during preclinical and clinical development. Furthermore, this chapter will highlight some of the translational challenges associated with elements of NPs and how these issues can only be addressed by detailed and novel pharmacology studies.
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Nanoparticle (NP) delivery to solid tumors has recently been questioned. To better understand the magnitude of NP tumor delivery, we reanalyzed published murine NP tumor pharmacokinetic (PK) data used in the Wilhelm et al. study. Studies included in their analysis reporting matched tumor and blood concentration versus time data were evaluated using classical PK endpoints and compared to the unestablished percent injected dose (%ID) in tumor metric from the Wilhelm et al. study. The %ID in tumor was poorly correlated with standard PK metrics that describe NP tumor delivery (AUCtumor/AUCblood ratio) and only moderately associated with maximal tumor concentration. The relative tumor delivery of NPs was ~100-fold greater as assessed by the standard AUCtumor/AUCblood ratio than by %ID in tumor. These results strongly suggest that PK metrics and calculations can influence the interpretation of NP tumor delivery and stress the need to properly validate novel PK metrics against traditional approaches.
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BACKGROUND: Glioblastoma-associated macrophages and microglia (GAMs) are the predominant immune cells in the tumor microenvironment. Activation of MerTK, a receptor tyrosine kinase, polarizes GAMs to an immunosuppressive phenotype, promoting tumor growth. Here, the role of MerTK inhibition in the glioblastoma microenvironment is investigated in vitro and in vivo. METHODS: Effects of MRX-2843 in glioblastoma microenvironment regulation were determined in vitro by cell viability, cytokine array, in vitro tube formation, Western blotting, and wound healing assays. A syngeneic GL261 orthotopic glioblastoma mouse model was used to evaluate the survival benefit of MRX-2843 treatment. Multiplex fluorescent immunohistochemistry was used to evaluate the expression of CD206, an anti-inflammatory marker on GAMs, and angiogenesis in murine brain tumor tissues. RESULTS: MRX-2843 inhibited cell growth and induced apoptosis in human glioblastoma cells and decreased protein expression of phosphorylated MerTK, AKT, and ERK, which are essential for cell survival signaling. Interleukin-8 and C-C motif chemokine ligand 2, the pro-glioma and pro-angiogenic cytokines, were decreased by MRX-2843. Decreased vascular formation and numbers of immunosuppressive (CD206+) GAMs were observed following MRX-2843 treatment in vivo, suggesting that in addition to alleviating immunosuppression, MRX-2843 also inhibits neoangiogenesis in the glioma microenvironment. These results were supported by a prolonged survival in the syngeneic mouse orthotopic GL261 glioblastoma model following MRX-2843 treatment. CONCLUSION: Our findings suggest that MRX-2843 has a therapeutic benefit via promoting GAM polarization away from immunosuppressive condition, inhibiting neoangiogenesis in the glioblastoma microenvironment and inducing tumor cell death.
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Current interstitial therapies for glioblastoma can overcome the blood-brain barrier but fail to optimally release therapy at a rate that stalls cancer reoccurrence. To address this lapse, acetalated dextran (Ace-DEX) nanofibrous scaffolds were used for their unique degradation rates that translate to a broad range of drug release kinetics. A distinctive range of drug release rates was illustrated via electrospun Ace-DEX or poly(lactic acid) (PLA) scaffolds. Scaffolds composed of fast, medium, and slow degrading Ace-DEX resulted in 14.1%, 2.9%, and 1.3% paclitaxel released per day. To better understand the impact of paclitaxel release rate on interstitial therapy, two clinically relevant orthotopic glioblastoma mouse models were explored: (1) a surgical model of resection and recurrence (resection model) and (2) a distant metastasis model. The effect of unique drug release was illustrated in the resection model when a 78% long-term survival was observed with combined fast and slow release scaffolds, in comparison to a survival of 20% when the same dose is delivered at a medium release rate. In contrast, only the fast release rate scaffold displayed treatment efficacy in the distant metastasis model. Additionally, the acid-sensitive Ace-DEX scaffolds were shown to respond to the lower pH conditions associated with GBM tumors, releasing more paclitaxel in vivo when a tumor was present in contrast to nonacid sensitive PLA scaffolds. The unique range of tunable degradation and stimuli-responsive nature makes Ace-DEX a promising drug delivery platform to improve interstitial therapy for glioblastoma.
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Antineoplásicos/uso terapêutico , Dextranos/química , Portadores de Fármacos/química , Glioblastoma/tratamento farmacológico , Paclitaxel/uso terapêutico , Poliésteres/química , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Camundongos Nus , Metástase Neoplásica/tratamento farmacológico , Paclitaxel/farmacocinética , Prevenção Secundária/métodos , Microambiente Tumoral/fisiologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The rapid advancement in the development of therapeutic proteins, including monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs), has created a novel mechanism to selectively deliver highly potent cytotoxic agents in the treatment of cancer. These agents provide numerous benefits compared to traditional small molecule drugs, though their clinical use still requires optimization. The pharmacology of mAbs/ADCs is complex and because ADCs are comprised of multiple components, individual agent characteristics and patient variables can affect their disposition. To further improve the clinical use and rational development of these agents, it is imperative to comprehend the complex mechanisms employed by antibody-based agents in traversing numerous biological barriers and how agent/patient factors affect tumor delivery, toxicities, efficacy, and ultimately, biodistribution. This review provides an updated summary of factors known to affect the disposition of mAbs/ADCs in development and in clinical use, as well as how these factors should be considered in the selection and design of preclinical studies of ADC agents in development.
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Pretargeting is an increasingly explored strategy to improve nanoparticle targeting, in which pretargeting molecules that bind both selected epitopes on target cells and nanocarriers are first administered, followed by the drug-loaded nanocarriers. Bispecific antibodies (bsAb) represent a promising class of pretargeting molecules, but how different bsAb formats may impact the efficiency of pretargeting remains poorly understood, in particular Fab valency and Fc receptor (FcR)-binding of bsAb. We found the tetravalent bsAb markedly enhanced PEGylated nanoparticle binding to target HER2+ cells relative to the bivalent bsAb in vitro. Pretargeting with tetravalent bsAb with abrogated FcR binding increased tumor accumulation of PEGylated liposomal doxorubicin (PLD) 3-fold compared to passively targeted PLD alone, and 5-fold vs pretargeting with tetravalent bsAb with normal FcR binding in vivo. Our work demonstrates that multivalency and elimination of FcRn recycling are both important features of pretargeting molecules, and further supports pretargeting as a promising nanoparticle delivery strategy.
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Anticorpos Biespecíficos , Antineoplásicos Imunológicos , Portadores de Fármacos , Neoplasias Experimentais , Polietilenoglicóis , Receptor ErbB-2/antagonistas & inibidores , Animais , Anticorpos Biespecíficos/química , Anticorpos Biespecíficos/farmacologia , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Feminino , Humanos , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , ômega-CloroacetofenonaRESUMO
Antibodies that specifically bind polyethylene glycol (PEG), i.e. anti-PEG antibodies (APA), are associated with reduced efficacy and increased risk of serious adverse events for several PEGylated therapeutics. Here, we explored the concept of using free PEG molecules to saturate circulating APA. Surprisingly, we found that 40â¯kDa free PEG effectively restored the prolonged circulation of PEGylated liposomes in the presence of high titers of pre-existing APA for at least 48â¯h in mice. In contrast, lower molecular weight free PEG (≤10â¯kDa) failed to restore circulation beyond a few hours. These in vivo results were consistent with estimates from a minimal physiologically based pharmacokinetic model. Importantly, the infusion of free PEG appeared to be safe in mice previously sensitized by injection of PEGylated liposomes, and free PEG did not elicit excess APA production even in mice with pre-existing adaptive immunity against PEG. Our results support further investigation of high molecular weight free PEG as a potential method to control and overcome high titers of APA, restoring the prolonged circulation of PEGylated liposomes and possibly other PEGylated therapeutics.
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Antibióticos Antineoplásicos/administração & dosagem , Anticorpos/imunologia , Doxorrubicina/administração & dosagem , Polietilenoglicóis/administração & dosagem , Administração Intravenosa , Animais , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Feminino , Lipossomos , Fígado/metabolismo , Camundongos Endogâmicos BALB C , Peso Molecular , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinéticaRESUMO
PURPOSE: The surface contamination levels of 5 commonly used hazardous drugs in hospital pharmacies are summarized, identifying practice patterns associated with contamination. METHODS: Contamination testing data were compiled to evaluate surface contaminants of 5 hazardous drugs (docetaxel, paclitaxel, cyclophosphamide, ifosfamide, and 5-fluorourcil). Data from 5,842 wipes over 6 years were collected from 338 hospital pharmacies. The contamination level for each drug was categorized as nondetectable (ND; ≤10 ng/ft2), low (between 10 and ≤100 ng/ft2), medium (between 100 and ≤1,000 ng/ft2) or high (>1,000 ng/ft2). Surface exposures for each drug were summarized based on location, contamination at first and subsequent wipe events, and the use of a closed system transfer device (CSTD). RESULTS: The majority of contamination results corresponded to locations at or near hazardous drug preparation, but also occurred in areas where hazardous drugs were not prepared. There was a higher incidence of contamination levels (high, medium, and low, respectively) at first wipe event (10.2%, 17.4%, and 17.7%) compared to subsequent wipe events (5.8%, 12.2%, and 13.6%) (p < 0.0001). There was a lower incidence of contamination levels at institutions that used CSTDs (6.3%, 12.8%, and 14.4%) compared to institutions that did not use CSTDs (14.2%, 17.9%, and 17.3%) (p < 0.0001). CONCLUSIONS: The majority of highest contamination levels corresponded to locations where hazardous drugs were prepared. While the rate of contamination was lower at subsequent wipe events and at institutions that used CSTDs, contamination was not completely eliminated in either scenario.
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Antineoplásicos/análise , Contaminação de Equipamentos/prevenção & controle , Substâncias Perigosas/análise , Serviço de Farmácia Hospitalar/normas , Composição de Medicamentos/métodos , Composição de Medicamentos/normas , Monitoramento Ambiental/métodos , Equipamentos e Provisões Hospitalares/normas , Humanos , Serviço de Farmácia Hospitalar/métodosRESUMO
INTRODUCTION: Intraperitoneal (IP) chemotherapy improves survival in ovarian cancer but its use has been limited by toxicity with cisplatin-based regimens. The primary objective of this study was to define the maximum tolerated dose and dose-limiting toxicity of intravenous (IV) oxaliplatin and IP docetaxel in women with recurrent ovarian, fallopian tube or peritoneal cancer. Secondary objectives were response rate, time to progression, symptom interference with quality of life, and pharmacokinetics. METHODS: Patients received a constant dose of oxaliplatin 75 mg/m2 IV on day 1 and docetaxel escalating from 50 mg/m2 IP on day 2 every 3 weeks using a 3 + 3 design. Treatment continued until disease progression, remission, or intolerable toxicity occurred. Plasma and IP samples were taken to determine drug concentrations. Patients completed the MD Anderson Symptom Inventory weekly. RESULTS: Twelve patients were included. The median number of cycles was 4 (range 2-6) with a median time to progression of 4.5 months. Among eight patients with measurable disease, the best responses were partial response in two patients, stable disease in five, and progressive disease in one. A total of 14 grade 3-4 toxicities were noted, most commonly hematologic. Four patients, all dose level 3, had six dose-limiting toxicities: two with prolonged neutropenia, one with infection, one with hyponatremia, and two with abdominal pain. Dose level 3 was therefore considered intolerable. The mean±SD ratio of docetaxel area under the curve (AUC) in IP fluid to AUC in plasma was 229±111. Symptom interference with life activities steadily decreased from cycle 1 to 5. CONCLUSIONS: Oxaliplatin 75 mg/m2 IV on day 1 and docetaxel 75 mg/m2 IP on day 2 was the maximum tolerated dose. Most patients had partial response or stable disease, even in a heavily pre-treated population. At this dose level, patient-reported outcomes demonstrate temporary but tolerable decrements in quality of life.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Qualidade de Vida , Administração Intravenosa , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Docetaxel/administração & dosagem , Neoplasias das Tubas Uterinas/patologia , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Oxaliplatina/administração & dosagem , Neoplasias Peritoneais/patologia , Prognóstico , Distribuição TecidualRESUMO
PURPOSE: Obesity may alter mononuclear phagocyte system (MPS) function and the pharmacology and efficacy of nanoparticles therapies, such as PEGylated liposomal doxorubicin (PLD). We aimed to evaluate the relationships between hormone and chemokine mediators of MPS function and the pharmacokinetic (PK) exposure of PLD in obese and normal weight patients with ovarian and endometrial cancer. METHODS: Hormone and chemokine mediators in obese and normal weight ovarian and endometrial cancer patients were measured. A separate pharmacology study was performed that evaluated the relationship between serum hormone concentrations, MPS function, and PK disposition of PLD in refractory ovarian cancer patients. RESULTS: Univariate analysis revealed a significant relationship between serum estradiol and body mass index (OR 8.64, 95% CI 2.67-28.0, p < 0.001). Estrone and testosterone concentrations were positively correlated with MPS function (ρ = 0.57 and 0.53, p = 0.14 and 0.18, respectively) and inversely correlated with PLD PK exposure (ρ = - 0.75 and - 0.76, respectively, p = 0.02 for both). CONCLUSIONS: Higher MPS function resulting in reduced PLD exposure is a potential mechanism for reduced efficacy of PLD and other nanoparticles observed in obese patients with cancer. PK simulations suggest higher doses of PLD are required in obese patients to achieve similar exposures as standard dosing in normal weight patients.
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Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/análogos & derivados , Neoplasias do Endométrio/patologia , Sistema Fagocitário Mononuclear/fisiopatologia , Nanopartículas/administração & dosagem , Obesidade/fisiopatologia , Neoplasias Ovarianas/patologia , Antibióticos Antineoplásicos/química , Estudos de Casos e Controles , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Neoplasias do Endométrio/tratamento farmacológico , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Nanopartículas/química , Neoplasias Ovarianas/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , PrognósticoRESUMO
Nanotechnology provides many solutions to improve conventional drug delivery and has a unique niche in the areas related to the specific targeting of the immune system, such as immunotherapies and vaccines. Preclinical studies in this field rely heavily on the combination of in vitro and in vivo methods to assess the safety and efficacy of nanotechnology platforms, nanoparticle-formulated drugs, and vaccines. While certain types of toxicities can be evaluated in vitro and good in vitro-in vivo correlation has been demonstrated for such tests, animal studies are still needed to address complex biological questions and, therefore, provide a unique contribution to establishing nanoparticle safety and efficacy profiles. The genetic, metabolic, mechanistic, and phenotypic diversity of currently available animal models often complicates both the animal choice and the interpretation of the results. This review summarizes current knowledge about differences in the immune system function and immunological responses of animals commonly used in preclinical studies of nanomaterials. We discuss challenges, highlight current gaps, and propose recommendations for animal model selection to streamline preclinical analysis of nanotechnology formulations.
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Sistema Imunitário/inervação , Modelos Animais , Nanoestruturas/química , Nanotecnologia , Animais , Sistema Imunitário/imunologiaRESUMO
Major advances in carrier-mediated agents (CMAs), which include nanoparticles, nanosomes, and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages, such as greater solubility, duration of exposure, and delivery to the site of action over their small molecule counterparts, there is substantial variability in systemic clearance and distribution, tumor delivery, and pharmacologic effects (efficacy and toxicity) of these agents. In this chapter, we focus on the analytical and phenotypic methods required to design a study that characterizes the pharmacokinetics (PK) and pharmacodynamics (PD) of all forms of these nanoparticle-based drug agents. These methods include separation of encapsulated and released drugs, ultrafiltration for measurement of non-protein bound active drug, microdialysis to measure intra-tumor drug concentrations, immunomagnetic separation and flow cytometry for sorting cell types, and evaluation of spatial distribution of drug forms relative to tissue architecture by mass spectrometry imaging and immunohistochemistry.