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1.
Artigo em Inglês | MEDLINE | ID: mdl-35953664

RESUMO

Quantitative Systems Pharmacology (QSP) modeling is increasingly applied in the pharmaceutical industry to influence decision making across a wide range of stages from early discovery to clinical development to post-marketing activities. Development of standards for how these models are constructed, assessed, and communicated is of active interest to the modeling community and regulators but is complicated by the wide variability in the structures and intended uses of the underlying models and the diverse expertise of QSP modelers. With this in mind, the IQ Consortium conducted a survey across the pharmaceutical/biotech industry to understand current practices for QSP modeling. This article presents the survey results and provides insights into current practices and methods used by QSP practitioners based on model type and the intended use at various stages of drug development. The survey also highlights key areas for future development including better integration with statistical methods, standardization of approaches towards virtual populations, and increased use of QSP models for late-stage clinical development and regulatory submissions.

2.
Br J Clin Pharmacol ; 88(4): 1430-1440, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-32621550

RESUMO

Quantitative systems pharmacology (QSP) is a relatively new discipline within modelling and simulation that has gained wide attention over the past few years. The application of QSP models spans drug-target identification and validation, through all drug development phases as well as clinical applications. Due to their detailed mechanistic nature, QSP models are capable of extrapolating knowledge to predict outcomes in scenarios that have not been tested experimentally, making them an important resource in experimental and clinical pharmacology. However, these models are complicated to work with due to their size and inherent complexity. This makes many applications of QSP models for simulation, parameter estimation and trial design computationally intractable. A number of techniques have been developed to simplify QSP models into smaller models that are more amenable to further analyses while retaining their accurate predictive capabilities. Different simplification techniques have different strengths and weaknesses and hence different utilities. Understanding the utilities of different methods is essential for selection of the best method for a particular situation. In this paper, we have created an overall framework for model simplification techniques that allows a natural categorisation of methods based on their utility. We provide a brief description of the concept underpinning the different methods and example applications. A summary of the utilities of methods is intended to provide a guide to modellers in their model endeavours to simplify these complicated models.


Assuntos
Farmacologia Clínica , Farmacologia , Simulação por Computador , Desenvolvimento de Medicamentos/métodos , Humanos , Modelos Biológicos , Farmacologia em Rede , Farmacologia/métodos
4.
Cureus ; 13(1): e12505, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33564513

RESUMO

Peritoneal tuberculosis is a rare disease with increasing incidence in recent years, especially in patients with an immunocompromised state and liver cirrhosis. We report the case of a 37-year-old male with a known history of liver cirrhosis who presented to the hospital with abdominal pain, abdominal distension, and was diagnosed with peritoneal tuberculosis. The diagnosis was made based on findings from a CT of the abdomen and histopathological findings of peritoneal tissue biopsy. He was started on ethambutol, isoniazid, pyrazinamide, and rifampin for six months.

5.
Clin Pharmacol Ther ; 109(3): 605-618, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32686076

RESUMO

Drug development in oncology commonly exploits the tools of molecular biology to gain therapeutic benefit through reprograming of cellular responses. In immuno-oncology (IO) the aim is to direct the patient's own immune system to fight cancer. After remarkable successes of antibodies targeting PD1/PD-L1 and CTLA4 receptors in targeted patient populations, the focus of further development has shifted toward combination therapies. However, the current drug-development approach of exploiting a vast number of possible combination targets and dosing regimens has proven to be challenging and is arguably inefficient. In particular, the unprecedented number of clinical trials testing different combinations may no longer be sustainable by the population of available patients. Further development in IO requires a step change in selection and validation of candidate therapies to decrease development attrition rate and limit the number of clinical trials. Quantitative systems pharmacology (QSP) proposes to tackle this challenge through mechanistic modeling and simulation. Compounds' pharmacokinetics, target binding, and mechanisms of action as well as existing knowledge on the underlying tumor and immune system biology are described by quantitative, dynamic models aiming to predict clinical results for novel combinations. Here, we review the current QSP approaches, the legacy of mathematical models available to quantitative clinical pharmacologists describing interaction between tumor and immune system, and the recent development of IO QSP platform models. We argue that QSP and virtual patients can be integrated as a new tool in existing IO drug development approaches to increase the efficiency and effectiveness of the search for novel combination therapies.


Assuntos
Alergia e Imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desenvolvimento de Medicamentos , Inibidores de Checkpoint Imunológico/uso terapêutico , Oncologia , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Biologia de Sistemas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Simulação por Computador , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/farmacocinética , Modelos Imunológicos , Terapia de Alvo Molecular , Neoplasias/imunologia , Neoplasias/metabolismo , Microambiente Tumoral
8.
Diagn Cytopathol ; 47(11): 1138-1144, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31313531

RESUMO

BACKGROUND: Endoscopic ultrasound (EUS) guided core needle biopsies (CNB) are increasingly being performed to diagnose solid pancreatic lesions. However, studies have been conflicting in terms of CNB improving diagnostic accuracy and procedural efficiency vs fine-needle aspiration (FNA), which this study aims to elucidate. METHODS: Data were prospectively collected on consecutive patients with solid pancreatic or peripancreatic lesions at a single tertiary care center from November 2015 to November 2016 that underwent either FNA or CNB. Patient demographics, characteristics of lesions, diagnostic accuracy, final and follow-up pathology, use of rapid on-site evaluation (ROSE), complications, and procedure variables were obtained. RESULTS: A total of 75 FNA and 48 CNB were performed; of these, 13 patients had both. Mean passes were lower with CNB compared to FNA (2.4 vs 2.9, P = .02). Use of ROSE was higher for FNA (97.3% vs 68.1%, P = .001). Mean procedure time was shorter with CNB (34.1 minutes vs 51.2 minutes, P = .02) and diagnostic accuracy was similar (89.2% vs 89.4%, P = .98). There was no difference in diagnostic accuracy when ROSE was performed for CNB vs not performed (93.5% vs 85.7%, P = .58). Additionally, diagnostic accuracy of combined FNA and CNB procedures was 92.3%, which was comparable to FNA (P = .73) or CNB (P = .52) alone. CONCLUSION: FNA and CNB had comparable safety and diagnostic accuracy. Use of CNB resulted in less number of passes and shorter procedure time as compared to FNA. Moreover, diagnostic accuracy for CNB with or without ROSE was similar.


Assuntos
Pâncreas , Neoplasias Pancreáticas , Idoso , Biópsia com Agulha de Grande Calibre , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Estudos Prospectivos
9.
Pancreas ; 48(1): 80-84, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30451791

RESUMO

OBJECTIVES: Surgery is the curative treatment for pancreatic ductal adenocarcinoma (PDA). Guidelines recommend utilizing a multidisciplinary pancreatic cancer conference (MDPC) in treatment; however, data are limited. The objective of this study was to assess the accuracy of an MDPC. METHODS: Patients with PDA presented at an MDPC were prospectively collected from April 2013 to August 2016. Patients were included if the MDPC predicted them to have resectable PDA and underwent upfront surgery. Secondary aims were to compare differences in tumor characteristics, time to surgery, and resection rates with patients prior to MDPC implementation (pre-MDPC). RESULTS: A total of 278 patients were presented at the MDPC. After excluding borderline and nonresectable cases, 91 patients were predicted as resectable on evaluation, and 70 were fit for surgery. The MDPC predicted resection in 91.4%. The MDPC had larger tumor size (32.6 vs 24.0 mm), greater proportion of stage II tumor, and a shorter time from diagnosis to resection (27.3 vs 35.5 days) compared with the pre-MDPC. Microscopically negative resections were similar between MDPC and pre-MDPC (85.9% vs 88.0%) despite advanced tumor size and stage. CONCLUSIONS: The MDPC demonstrates a high resection rate. Compared with a pre-MDPC, MDPC provides shorter time to surgery and selects for advanced tumors.


Assuntos
Carcinoma Ductal Pancreático/cirurgia , Conferências de Consenso como Assunto , Pancreatectomia/métodos , Neoplasias Pancreáticas/cirurgia , Idoso , Carcinoma Ductal Pancreático/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Pancreatectomia/estatística & dados numéricos , Neoplasias Pancreáticas/diagnóstico , Prognóstico , Estudos Prospectivos
11.
Hepatology ; 68(4): 1298-1307, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29672891

RESUMO

Well-tolerated, ribavirin-free, pangenotypic hepatitis C virus (HCV) treatments for transplant recipients remain a high priority. Once-daily glecaprevir/pibrentasvir demonstrates high rates of sustained virologic response at 12 weeks posttreatment (SVR12) across all major HCV genotypes (GTs). This trial evaluated the safety and efficacy of glecaprevir/pibrentasvir for patients with chronic HCV GT1-6 infection who had received a liver or kidney transplant. MAGELLAN-2 was a phase 3, open-label trial conducted in patients who were ≥3 months posttransplant. Patients without cirrhosis who were HCV treatment-naive (GT1-6) or treatment-experienced (GT1, 2, 4-6; with interferon-based therapy with or without sofosbuvir, or sofosbuvir plus ribavirin) received glecaprevir/pibrentasvir (300/120 mg) once daily for 12 weeks. The primary endpoint compared the percentage of patients receiving glecaprevir/pibrentasvir with SVR12 to a historic SVR12 rate based on the standard of care. Safety of glecaprevir/pibrentasvir was assessed. In total, 80 liver transplant and 20 kidney transplant patients participated in the trial. Most patients had no or minimal fibrosis (80% had fibrosis scores F0-F1) and were infected with HCV GT1 (57%) or GT3 (24%). The overall SVR12 was 98% (n/N = 98/100; 95% confidence interval, 95.3%-100%), which exceeded the prespecified historic standard-of-care SVR12 threshold of 94%. One patient experienced virologic failure. One patient discontinued because of an adverse event considered to be unrelated to treatment; this patient achieved SVR12. Adverse events were mostly mild in severity, and laboratory abnormalities were infrequent. CONCLUSION: Once-daily glecaprevir/pibrentasvir for 12 weeks is a well-tolerated and efficacious, ribavirin-free treatment for patients with chronic HCV GT1-6 infection who have received a liver or kidney transplant. (ClinicalTrials.gov NCT02692703.) (Hepatology 2018; 00:000-000).


Assuntos
Benzimidazóis/administração & dosagem , Hepatite C Crônica/tratamento farmacológico , Transplante de Rim , Transplante de Fígado , Quinoxalinas/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Idoso , Ácidos Aminoisobutíricos , Ciclopropanos , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Rejeição de Enxerto , Sobrevivência de Enxerto , Hepatite C Crônica/diagnóstico , Humanos , Internacionalidade , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Pessoa de Meia-Idade , Prognóstico , Prolina/análogos & derivados , Pirrolidinas , Medição de Risco , Transplantados , Resultado do Tratamento
12.
Clin Infect Dis ; 67(7): 1010-1017, 2018 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-29566246

RESUMO

Background: Once-daily glecaprevir coformulated with pibrentasvir (glecaprevir/pibrentasvir) demonstrated high rates of sustained virologic response 12 weeks after treatment (SVR12) in patients with hepatitis C virus (HCV) genotype 1-6 infection. This phase 3 study evaluated the efficacy and safety of glecaprevir/pibrentasvir in patients with chronic HCV genotype 1-6 and human immunodeficiency virus type 1 (HIV-1) coinfection, including patients with compensated cirrhosis. Methods: EXPEDITION-2 was a phase 3, multicenter, open-label study evaluating glecaprevir/pibrentasvir (300 mg/120 mg) in HCV genotype 1-6/HIV-1-coinfected adults without and with compensated cirrhosis for 8 and 12 weeks, respectively. Patients were either HCV treatment-naive or experienced with sofosbuvir, ribavirin, or interferon, and antiretroviral therapy (ART) naive or on a stable ART regimen. Treatment-experienced genotype 3-infected patients were excluded. The primary endpoint was the SVR12 rate. Results: In total, 153 patients were enrolled, including 16 (10%) with cirrhosis. The SVR12 rate was 98% (n = 150/153; 95% confidence interval, 95.8-100), with no virologic failures in 137 patients treated for 8 weeks. One genotype 3-infected patient with cirrhosis had on-treatment virologic failure. Most adverse events were mild in severity; 4 patients (2.6%) had serious adverse events, all deemed unrelated to glecaprevir/pibrentasvir. Treatment discontinuation was rare (<1%). All patients treated with ART maintained HIV-1 suppression (<200 copies/mL) during treatment. Conclusions: Glecaprevir/pibrentasvir for 8 weeks in noncirrhotic and 12 weeks in cirrhotic patients is a highly efficacious and well-tolerated treatment for HCV/HIV-1 coinfection, regardless of baseline HCV load or prior treatment with interferon or sofosbuvir. Clinical trial registration: NCT02738138.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Infecções por HIV/tratamento farmacológico , Hepatite C/tratamento farmacológico , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Animais , Coinfecção , Combinação de Medicamentos , Feminino , HIV-1 , Humanos , Cirrose Hepática , Masculino , Adulto Jovem
13.
Clin Appl Thromb Hemost ; 24(4): 669-676, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28731370

RESUMO

A well-accepted test for monitoring anticoagulation by enoxaparin is not currently available. As inadequate dosing may result in thrombosis or bleeding, a clinical need exists for a suitable test. Previous in silico and in vitro studies have identified factor Xa as an appropriate activating agent, and the phospholipid Actin FS as a cofactor for a Xa clotting time (TenaCT) test. A proof-of-concept study was designed to (1) explore the reproducibility of the TenaCT test and (2) explore factors that could affect the performance of the test. In vitro clotting time tests were carried out using plasma from 20 healthy volunteers. The effect of enoxaparin was determined at concentrations of 0.25, 0.50, and 1.0 IU/mL. Clotting times for the volunteers were significantly prolonged with increasing enoxaparin concentrations. Clotting times were significantly shortened for frozen plasma samples. No significant differences in prolongation of clotting times were observed between male and female volunteers or between the 2 evaluated age groups. The clotting times were consistent between 2 separate occasions. The TenaCT test was able to distinguish between the subtherapeutic and therapeutic concentrations of enoxaparin. Plasma should not be frozen prior to performing the test, without defining a frozen plasma reference range. This study provided proof-of-concept for a Xa-based test that can detect enoxaparin dose effects, but additional studies are needed to further develop the test.


Assuntos
Anticoagulantes/uso terapêutico , Testes de Coagulação Sanguínea/métodos , Coagulação Sanguínea/efeitos dos fármacos , Enoxaparina/uso terapêutico , Fator Xa/metabolismo , Adolescente , Adulto , Anticoagulantes/farmacologia , Enoxaparina/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Case Rep Gastrointest Med ; 2017: 5480562, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29109874

RESUMO

A 67-year-old woman with a long-standing history of recurrent dysphagia and esophageal strictures failed to respond to aggressive antireflux management. She required multiple dilations for symptomatic strictures that were discovered throughout the esophagus. Intralesional, topical, and systemic glucocorticoid therapies were utilized without resolution in symptoms. Several years after initial presentation, histopathology ultimately demonstrated lichenoid features and a diagnosis of esophageal lichen planus (ELP) was confirmed. However, as her symptoms had already become significantly disabling with severe strictures that carried an increased risk of endoscopic complications with dilation, she ultimately decided to undergo an esophagectomy for definitive treatment. Moreover, ELP may often go unrecognized for several years. Clinicians should consider ELP in the differential for dysphagia in middle- to elderly-aged women with or without a known history of lichen planus (LP) especially for those with findings of multiple or proximal strictures.

16.
Dig Liver Dis ; 48(7): 817-9, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27038705

RESUMO

BACKGROUND AND AIMS: IgG4-mediated pouchitis was first described in 2011. The aetiology and pathogenesis of IgG4-associated pouchitis is unknown. Over the last four years, less than seventy cases of IgG-associated pouchitis have been reported from a pouchitis clinic in Cleveland. METHODS: We report the first two cases of IgG4-associated pouchitis from our inflammatory bowel disease clinic and outside of Cleveland. CONCLUSION: This highlights the fact that this entity could be more common than we think. It is important for general gastroenterologists to think about IgG4-mediated disease if the patient has refractory pouchitis, so early diagnosis and referral can be made. This would avoid the cost of expensive therapy and minimize antibiotic use which is what happened in our cases prior to this diagnosis being made.


Assuntos
Doenças Autoimunes/sangue , Colite Ulcerativa/complicações , Bolsas Cólicas/patologia , Imunoglobulina G/sangue , Pouchite/diagnóstico , Proctocolectomia Restauradora/efeitos adversos , Adulto , Antibacterianos/uso terapêutico , Endoscopia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pouchite/tratamento farmacológico , Recidiva
17.
Pharm Res ; 32(10): 3391-402, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26129765

RESUMO

PURPOSE: Dosing of enoxaparin, like other anticoagulants, may result in bleeding following excessive doses and clot formation if the dose is too low. We recently showed that a factor Xa based clotting time test could potentially assess the effect of enoxaparin on the clotting system. However, the test did not perform well in subsequent individuals and effectiveness of an exogenous phospholipid, Actin FS, in reducing the variability in the clotting time was assessed. The aim of this work was to conduct an adaptive pilot study to determine the range of concentrations of Xa and Actin FS to take forward into a proof-of-concept study. METHODS: A nonlinear parametric function was developed to describe the response surface over the factors of interest. An adaptive method was used to estimate the parameters using a D-optimal design criterion. In order to provide a reasonable probability of observing a success of the clotting time test, a P-optimal design criterion was incorporated using a loss function to describe the hybrid DP-optimality. RESULTS: The use of adaptive DP-optimality method resulted in an efficient estimation of model parameters using data from only 6 healthy volunteers. The use of response surface modelling identified a range of sets of Xa and Actin FS concentrations, any of which could be used for the proof-of-concept study. CONCLUSIONS: This study shows that parsimonious adaptive DP-optimal designs may provide both precise parameter estimates for response surface modelling as well as clinical confidence in the potential benefits of the study.


Assuntos
Anticoagulantes/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Enoxaparina/uso terapêutico , Adulto , Testes de Coagulação Sanguínea/métodos , Inibidores do Fator Xa/uso terapêutico , Hemorragia/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Projetos de Pesquisa , Adulto Jovem
18.
Toxicon ; 61: 94-104, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23151381

RESUMO

Snake venoms contain toxins that activate the coagulation network and cause venom-induced consumption coagulopathy. A previously developed mathematical model of the coagulation network was refined and used to describe and predict the time course of changes in the coagulation factors following envenomation by Brown snake (Pseudonaja spp.), Tiger snake (Notechis scutatus), Rough-scaled snake (Tropidechis carinatus) and Hoplocephalus spp. (Stephens banded, Pale headed and Broad headed). Simulations of the time course of the change in coagulation factors were compared to data obtained from a large prospective study of Australian snake bites - the Australian Snakebite Project. The model predictions were also compared against data for partial and complete VICC obtained from the same study. The model simulations were used to understand the differences in consumption and recovery of clotting factors in partial versus complete VICC as well as among bites from different snake types. The model suggested that the venoms were absorbed almost instantaneously and provided a reasonable prediction of the observed concentration of clotting factors over time in patients bitten by Australian elapid snakes. The model predictions suggested a higher consumption of factors (fibrinogen, II and IX in particular) in patients with complete VICC compared to those with partial VICC. The model also predicted that snakes with "Xa-like" venoms may produce a less severe VICC than snakes with "Xa:Va-like" venoms.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Venenos Elapídicos/farmacologia , Austrália , Fatores de Coagulação Sanguínea/farmacologia , Estudos de Coortes , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/induzido quimicamente , Humanos , Modelos Estatísticos , Protrombina/fisiologia , Mordeduras de Serpentes/sangue
19.
Pharm Res ; 29(1): 225-35, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21822767

RESUMO

PURPOSE: Dosing of the anticoagulant enoxaparin may result in bleeding following excessive doses or thrombosis if dose is too low. Rarely, anti-Xa activity is used to assess the dose for enoxaparin, but its utility to predict clotting or bleeding remains uncertain. We aimed to develop a clotting time test to monitor enoxaparin therapy. METHODS: A previously developed mathematical model of the coagulation network was used to identify suitable targets for monitoring enoxaparin therapy. In vitro experiments were then carried out to demonstrate proof of mechanism of the clotting time test activated by the new target activator. RESULTS: Using the mathematical model, we identified Xa as a plausible activating agent for a clotting time test for enoxaparin. In vitro experiments showed a prolongation of the Xa clotting time of 4.6-fold in the presence of enoxaparin (0.5 IU/ml) where 10 nM Xa was used to activate clotting. CONCLUSIONS: Using both simulations and in vitro experiments, we provide a proof of mechanism for the Xa clotting time (XaCT) test, which can be considered for further development to provide a biomarker of the effect of enoxaparin on the clotting system.


Assuntos
Anticoagulantes/uso terapêutico , Testes de Coagulação Sanguínea/métodos , Monitoramento de Medicamentos/métodos , Enoxaparina/uso terapêutico , Inibidores do Fator Xa , Anticoagulantes/efeitos adversos , Biomarcadores/sangue , Coagulação Sanguínea/efeitos dos fármacos , Enoxaparina/efeitos adversos , Humanos , Modelos Biológicos , Trombose/tratamento farmacológico
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