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  • 1
    Language: English
    In: Pharmaceutics, 2017-09-26, Vol.9 (4), p.41
    Description: Most marketed drugs are administered orally, despite the complex process of oral absorption that is difficult to predict. Oral bioavailability is dependent on the interplay between many processes that are dependent on both compound and physiological properties. Because of this complexity, computational oral physiologically-based pharmacokinetic (PBPK) models have emerged as a tool to integrate these factors in an attempt to mechanistically capture the process of oral absorption. These models use inputs from in vitro assays to predict the pharmacokinetic behavior of drugs in the human body. The most common oral PBPK models are compartmental approaches, in which the gastrointestinal tract is characterized as a series of compartments through which the drug transits. The focus of this review is on the development of oral absorption PBPK models, followed by a brief discussion of the major applications of oral PBPK models in the pharmaceutical industry.
    Subject(s): Drug therapy ; food-effect ; formulation simulation ; Kinetics ; oral absorption ; pH effect ; Pharmacology ; physiologically-based pharmacokinetic modeling ; Review
    ISSN: 1999-4923
    E-ISSN: 1999-4923
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 2
    Language: English
    In: Pharmaceutics, 2020-07-17, Vol.12 (7), p.672
    Description: The bioavailability of an orally administered small molecule is often dictated by drug-specific physicochemical characteristics and is influenced by many biological processes. For example, in fed or fasted conditions, the transit time within the gastrointestinal tract can vary, confounding the ability to predict the oral absorption. As such, the effects of food on the pharmacokinetics of compounds in the various biopharmaceutics classification system (BCS) classes need to be assessed. The consumption of food leads to physiological changes, including fluctuations in the gastric and intestinal pH, a delay in gastric emptying, an increased bile secretion, and an increased splanchnic and hepatic blood flow. Despite the significant impact of a drug’s absorption and dissolution, food effects have not been fully studied and are often overlooked. Physiologically-based pharmacokinetic (PBPK) models can be used to mechanistically simulate a compound’s pharmacokinetics under fed or fasted conditions, while integrating drug properties such as solubility and permeability. This review discusses the PBPK models published in the literature predicting the food effects, the models’ strengths and shortcomings, as well as future steps to mitigate the current knowledge gap. We observed gaps in knowledge which limits the ability of PBPK models to predict the negative food effects and food effects in the pediatric population. Overall, the further development of PBPK models to predict food effects will provide a mechanistic basis to understand a drug’s behavior in fed and fasted conditions, and will help enable the drug development process.
    Subject(s): Bile ; Bioavailability ; Clinical trials ; Drug dosages ; Drug interactions ; Enzymes ; Food ; food effects ; mathematical modeling ; Meals ; Metabolism ; Motility ; oral absorption ; Permeability ; Pharmaceuticals ; Pharmacokinetics ; physiologically-based pharmacokinetic model ; Physiology ; Regulatory agencies ; Review ; Small intestine ; Stomach
    ISSN: 1999-4923
    E-ISSN: 1999-4923
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 3
    Language: English
    In: Journal of medicinal chemistry, 2012-05-10, Vol.55 (9), p.4101-4113
    Description: A series of compounds were designed and synthesized as antagonists of cIAP1/2, ML-IAP, and XIAP based on the N-terminus, AVPI, of mature Smac. Compound 1 (GDC-0152) has the best profile of these compounds; it binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domains of cIAP1 and cIAP2 with K i values of 28, 14, 17, and 43 nM, respectively. These compounds promote degradation of cIAP1, induce activation of caspase-3/7, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Compound 1 inhibits tumor growth when dosed orally in the MDA-MB-231 breast cancer xenograft model. Compound 1 was advanced to human clinical trials, and it exhibited linear pharmacokinetics over the dose range (0.049 to 1.48 mg/kg) tested. Mean plasma clearance in humans was 9 ± 3 mL/min/kg, and the volume of distribution was 0.6 ± 0.2 L/kg.
    Subject(s): Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Baculoviral IAP Repeat-Containing 3 Protein ; Binding, Competitive ; Breast Neoplasms - drug therapy ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Caspases - metabolism ; Cell Line, Tumor ; Cell Survival - drug effects ; Clinical Trials, Phase I as Topic ; Female ; Humans ; Inhibitor of Apoptosis Proteins - antagonists & inhibitors ; Inhibitor of Apoptosis Proteins - metabolism ; Male ; Thiadiazoles - chemical synthesis ; Thiadiazoles - chemistry ; Thiadiazoles - pharmacokinetics ; Thiadiazoles - pharmacology ; Ubiquitin-Protein Ligases
    ISSN: 0022-2623
    E-ISSN: 1520-4804
    Source: Hellenic Academic Libraries Link
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  • 4
    Language: English
    In: The AAPS journal, 2013-08-14, Vol.15 (4), p.1109-1118
    Description: In the pharmaceutical industry, salt is commonly used to improve the oral bioavailability of poorly soluble compounds. Currently, there is a limited understanding on the solubility requirement for salts that will translate to improvement in oral exposure. Despite the obvious need, there is very little research reported in this area mainly due to the complexity of such a system. To our knowledge, no report has been published to guide this important process and salt solubility requirement still remains unanswered. Physiologically based pharmacokinetic (PBPK) modeling offers a means to dynamically integrate the complex interplay of the processes determining oral absorption. A sensitivity analysis was performed using a PBPK model describing phenytoin to determine a solubility requirement for phenytoin salts needed to achieve optimal oral bioavailability for a given dose. Based on the analysis, it is predicted that phenytoin salts with solubility greater than 0.3 mg/mL would show no further increases in oral bioavailability. A salt screen was performed using a variety of phenytoin salts. The piperazine and sodium salts showed the lowest and highest aqueous solubility and were tested in vivo . Consistent with our analysis, we observed no significant differences in oral bioavailability for these two salts despite an approximate 60 fold difference in solubility. Our study illustrates that higher solubility salts sometimes provide no additional improvements in oral bioavailability and PBPK modeling can be utilized as an important tool to provide guidance to the salt selection and define a salt solubility requirement.
    Subject(s): Analysis ; Animals ; bioavailability ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Biotechnology ; Case studies ; general ; Male ; Models, Biological ; oral absorption ; pharmacokinetic ; Pharmacology/Toxicology ; Pharmacy ; Phenytoin ; Phenytoin - chemistry ; Phenytoin - pharmacokinetics ; physiological model ; Piperazines - chemistry ; Piperazines - pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Research Article ; Salts - chemistry ; Salts - pharmacokinetics ; Solubility ; X-Ray Diffraction - methods
    ISSN: 1550-7416
    E-ISSN: 1550-7416
    Source: PubMed Central
    Source: Alma/SFX Local Collection
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  • 5
    Language: English
    In: Biopharmaceutics & drug disposition, 2016-03, Vol.37 (2), p.75-92
    Description: The mechanisms of absorption, distribution, metabolism and elimination of small and large molecule therapeutics differ significantly from one another and can be explored within the framework of a physiologically based pharmacokinetic (PBPK) model. This paper briefly reviews fundamental approaches to PBPK modeling, in which drug kinetics within tissues and organs are explicitly represented using physiologically meaningful parameters. The differences in PBPK models applied to small/large molecule drugs are highlighted, thus elucidating differences in absorption, distribution and elimination properties between these two classes of drugs in a systematic manner. The absorption of small and large molecules differs with respect to their common extravascular routes of delivery (oral versus subcutaneous). The role of the lymphatic system in drug distribution, and the involvement of tissues as sites of elimination (through catabolism and target mediated drug disposition) are unique features of antibody distribution and elimination that differ from small molecules, which are commonly distributed into the tissues but are eliminated primarily by liver metabolism. Fundamental differences exist in the ability to predict human pharmacokinetics based upon preclinical data due to differing mechanisms governing small and large molecule disposition. These differences have influence on the evolving utilization of PBPK modeling in the discovery and development of small and large molecule therapeutics. Copyright © 2015 John Wiley & Sons, Ltd.
    Subject(s): Animals ; Antibodies ; Antibodies, Monoclonal - pharmacokinetics ; Biopharmaceutics ; Health aspects ; Humans ; Models ; Models, Biological ; PBPK ; small molecules ; Viral antibodies
    ISSN: 0142-2782
    E-ISSN: 1099-081X
    Source: Hellenic Academic Libraries Link
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  • 6
    Language: English
    In: The Journal of biological chemistry, 2009-12-11, Vol.284 (50), p.34553-34560
    Description: Proapoptotic receptor agonists cause cellular demise through the activation of the extrinsic and intrinsic apoptotic pathways. Inhibitor of apoptosis (IAP) proteins block apoptosis induced by diverse stimuli. Here, we demonstrate that IAP antagonists in combination with Fas ligand (FasL) or the death receptor 5 (DR5) agonist antibody synergistically stimulate death in cancer cells and inhibit tumor growth. Single-agent activity of IAP antagonists relies on tumor necrosis factor-α signaling. By contrast, blockade of tumor necrosis factor-α does not affect the synergistic activity of IAP antagonists with FasL or DR5 agonist antibody. In most cancer cells, proapoptotic receptor agonist-induced cell death depends on amplifying the apoptotic signal via caspase-8-mediated activation of Bid and subsequent activation of the caspase-9-dependent mitochondrial apoptotic pathway. In the investigated cancer cell lines, induction of apoptosis by FasL or DR5 agonist antibody can be inhibited by knockdown of Bid. However, knockdown of X chromosome-linked IAP (XIAP) or antagonism of XIAP allows FasL or DR5 agonist antibody to induce activation of effector caspases efficiently without the need for mitochondrial amplification of the apoptotic signal and thus rescues the effect of Bid knockdown in these cells.
    Subject(s): Animals ; Apoptosis - physiology ; BH3 Interacting Domain Death Agonist Protein - genetics ; BH3 Interacting Domain Death Agonist Protein - metabolism ; Caspases - metabolism ; Cell Death - physiology ; Cell Line, Tumor ; Etanercept ; Fas Ligand Protein - metabolism ; Humans ; Immunoglobulin G - genetics ; Immunoglobulin G - metabolism ; Mechanisms of Signal Transduction ; Mice ; Receptors, TNF-Related Apoptosis-Inducing Ligand - agonists ; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism ; Receptors, Tumor Necrosis Factor - genetics ; Receptors, Tumor Necrosis Factor - metabolism ; RNA, Small Interfering - genetics ; RNA, Small Interfering - metabolism ; Signal Transduction - physiology ; Transplantation, Heterologous ; Tumor Necrosis Factor-alpha - metabolism ; X-Linked Inhibitor of Apoptosis Protein - antagonists & inhibitors ; X-Linked Inhibitor of Apoptosis Protein - genetics ; X-Linked Inhibitor of Apoptosis Protein - metabolism
    ISSN: 0021-9258
    E-ISSN: 1083-351X
    Source: HighWire Press (Free Journals)
    Source: PubMed Central
    Source: Alma/SFX Local Collection
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  • 7
    Language: English
    In: BMC cancer, 2022-04-28, Vol.22 (1), p.468-468
    Description: Research in treatment of non-small cell lung cancer (NSCLC) has shown promising results with stereotactic ablative radiotherapy (SABR) of oligometastatic disease, wherein distant disease may be limited to one or a few distant organs by host factors. Traditionally, PET/CT has been used in detecting metastatic disease and avoiding futile surgical intervention, however, sensitivity and specificity is limited to only 81 and 79%, respectively. Mediastinal staging still identifies occult nodal disease in up to 20% of NSCLC patients initially thought to be operative candidates. Endobronchial ultrasound and transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive tool for the staging and diagnosis of thoracic malignancy. When EBUS is combined with endoscopic ultrasound using the same bronchoscope (EUS-B), the diagnostic sensitivity and negative predictive value increase to 84 and 97%, respectively. Endoscopic staging in patients with advanced disease has never been studied, but may inform treatment if a curative SABR approach is being taken. This is a multi-centre, prospective, cohort study with two-stage design. In the first stage, 10 patients with oligometastatic NSCLC (lung tumour ± hilar/mediastinal lymphadenopathy) with up to 5 synchronous metastases will be enrolled An additional 19 patients will be enrolled in the second stage if rate of treatment change is greater than 10% in the first stage. Patients will be subject to EBUS or combined modality EBUS/EUS-B to assess bilateral lymph node stations using a N3 to N2 to N1 progression. Primary endpoint is defined as the rate of change to treatment plan including change from SABR to conventional dose radiation, change in mediastinal radiation field, and change from curative to palliative intent treatment. If a curative approach with SABR for oligometastatic disease is being explored, invasive mediastinal staging may guide treatment and prognosis. This study will provide insight into the use of endoscopic mediastinal staging in determining changes in treatment plan of NSCLC. Results will inform the design of future phase II trials. Clinicaltrials.gov identifier NCT04852588. Date of registration: April 19, 2021. 1.1 on December 9, 2021.
    Subject(s): Carcinoma, Non-Small-Cell Lung - pathology ; Cohort Studies ; Endobronchial ultrasound (EBUS) ; Endoscopic ultrasound (EUS) ; Humans ; Lung Neoplasms - pathology ; Lung Neoplasms - radiotherapy ; Lymphatic Metastasis - radiotherapy ; Neoplasm Staging ; Non-small cell lung cancer (NSCLC) ; Oligometastatic disease ; Positron Emission Tomography Computed Tomography ; Prospective Studies ; Stereotactic ablative radiotherapy (SABR)
    E-ISSN: 1471-2407
    Source: BioMedCentral Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 8
    Language: English
    In: Clinical pharmacokinetics, 2015-12-21, Vol.55 (6), p.735-749
    Description: Background and Objectives Physiologically based pharmacokinetic (PBPK) modeling for itraconazole has been challenging due to highly variable in vitro d ata used for ‘bottom-up’ model building. Under-prediction of pharmacokinetics and drug–drug interactions (DDIs) following multiple doses of itraconazole has limited the use of PBPK model simulation to aid an itraconazole clinical DDI study design. The aim of this work is to develop an itraconazole PBPK model predominantly using a ‘top-down’ approach to enable a more accurate pharmacokinetic and DDI prediction. Methods An itraconazole PBPK model describing itraconazole and hydroxyl-itraconazole (OH-ITZ) was constructed in Simcyp ® . The key parameters that govern the pharmacokinetic profile, including non-linear clearance (i.e., maximum rate of reaction [ V max ] and the Michaelis-Menten constant [ K m ]) and volume of distribution for both itraconazole and OH-ITZ, were redefined by leveraging existing in vivo data. Model verification was performed by comparing the simulated itraconazole and OH-ITZ pharmacokinetic profiles with the observed clinical data. Finally, the model was used to simulate clinical DDIs between itraconazole and midazolam. Results The developed PBPK model well-described the pharmacokinetics of itraconazole and OH-ITZ, and particularly captured their accumulation after repeated doses of itraconazole. This was verified with the observed data from 29 clinical studies where itraconazole solution or capsule was given as a single or multiple dose. The predicted DDI between itraconazole and midazolam was within 1.25-fold of the observed data for seven of ten studies and within 1.5-fold for nine of ten studies. Conclusion The improvement of the itraconazole PBPK model increased our confidence in using PBPK model simulations to optimize clinical itraconazole DDI study design.
    Subject(s): Computer Simulation ; Cytochrome P-450 CYP3A - metabolism ; Dose-Response Relationship, Drug ; Drug Interactions ; Fasting ; Humans ; Internal Medicine ; Itraconazole - pharmacokinetics ; Medicine ; Medicine & Public Health ; Midazolam - pharmacology ; Models, Biological ; Original Research Article ; Pharmacology/Toxicology ; Pharmacotherapy
    ISSN: 0312-5963
    E-ISSN: 1179-1926
    Source: Alma/SFX Local Collection
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  • 9
    Language: English
    In: Clinical pharmacokinetics, 2014-09-16, Vol.54 (1), p.81-93
    Description: Background and Objectives Monomethyl auristatin E (MMAE, a cytotoxic agent), upon releasing from valine-citrulline-MMAE (vc-MMAE) antibody-drug conjugates (ADCs), is expected to behave like small molecules. Therefore, evaluating the drug–drug interaction (DDI) potential associated with MMAE is important in the clinical development of ADCs. The objective of this work was to build a physiologically based pharmacokinetic (PBPK) model to assess MMAE–drug interactions for vc-MMAE ADCs. Methods A PBPK model linking antibody-conjugated MMAE (acMMAE) to its catabolite unconjugated MMAE associated with vc-MMAE ADCs was developed using a mixed ‘bottom-up’ and ‘top-down’ approach. The model was developed using in silico and in vitro data and in vivo pharmacokinetic data from anti-CD22-vc-MMAE ADC. Subsequently, the model was validated using clinical pharmacokinetic data from another vc-MMAE ADC, brentuximab vedotin. Finally, the verified model was used to simulate the results of clinical DDI studies between brentuximab vedotin and midazolam, ketoconazole, and rifampicin. Results The pharmacokinetic profile of acMMAE and unconjugated MMAE following administration of anti-CD22-vc-MMAE was well described by simulations using the developed PBPK model. The model’s performance in predicting unconjugated MMAE pharmacokinetics was verified by successful simulation of the pharmacokinetic profile following brentuximab vedotin administration. The model simulated DDIs, expressed as area under the concentration-time curve (AUC) and maximum concentration ( C max ) ratios, were well within the two-fold of the observed data from clinical DDI studies. Conclusions This work is the first demonstration of the use of PBPK modelling to predict MMAE-based DDI potential. The described model can be extended to assess the DDI potential of other vc-MMAE ADCs.
    Subject(s): Analysis ; Antibody-drug conjugates ; Antimitotic agents ; Antineoplastic agents ; Computer Simulation ; Dosage and administration ; Drug Interactions ; Humans ; Immunoconjugates - pharmacokinetics ; Immunoconjugates - pharmacology ; Internal Medicine ; Ketoconazole - pharmacokinetics ; Ketoconazole - pharmacology ; Medicine ; Medicine & Public Health ; Midazolam - pharmacokinetics ; Midazolam - pharmacology ; Models, Biological ; Oligopeptides - pharmacokinetics ; Oligopeptides - pharmacology ; Original Research Article ; Pharmacokinetics ; Pharmacology/Toxicology ; Pharmacotherapy ; Research ; Rifampin - pharmacokinetics ; Rifampin - pharmacology
    ISSN: 0312-5963
    E-ISSN: 1179-1926
    Source: Alma/SFX Local Collection
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  • 10
    Language: English
    In: ACS medicinal chemistry letters, 2015-03-12, Vol.6 (3), p.276-281
    Description: A minor structural change to tertiary sulfonamide RORc ligands led to distinct mechanisms of action. Co-crystal structures of two compounds revealed mechanistically consistent protein conformational changes. Optimized phenylsulfonamides were identified as RORc agonists while benzylsulfonamides exhibited potent inverse agonist activity. Compounds behaving as agonists in our biochemical assay also gave rise to an increased production of IL-17 in human PBMCs whereas inverse agonists led to significant suppression of IL-17 under the same assay conditions. The most potent inverse agonist compound showed 〉180-fold selectivity over the ROR isoforms as well as all other nuclear receptors that were profiled.
    Subject(s): agonist ; IL-17 ; inverse agonist ; Letter ; PBMC ; RORc ; RORγ ; TH17
    ISSN: 1948-5875
    E-ISSN: 1948-5875
    Source: Hellenic Academic Libraries Link
    Source: PubMed Central
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