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Xiajing Gong, Meng Hu, Liang Zhao
Additional value can be potentially created by applying big data tools to address pharmacometric problems. The performances of machine learning (ML) methods and the Cox regression model were evaluated based on simulated time-to-event data synthesized under various preset scenarios, i.e., with linear vs. nonlinear and dependent vs. independent predictors in the proportional hazard function, or with high-dimensional data featured by a large number of predictor variables. Our results showed that ML-based methods outperformed the Cox model in prediction performance as assessed by concordance index and in identifying the preset influential variables for high-dimensional data...
March 13, 2018: Clinical and Translational Science
Peijuan Zhu, Sherwin K B Sy, Andrej Skerjanec
This article provides an overview of four case studies to demonstrate the utility of pharmacometric analysis in biosimilar development to help design sensitive clinical pharmacology studies for the demonstration of biosimilarity. The two major factors that determine the sensitivity of a clinical pharmacokinetic/pharmacodynamic (PK/PD) study to demonstrate biosimilarity are the size of the potential difference to be detected (signal) and the inter-subject variability (noise), both of which can be characterized and predicted using pharmacometric approaches...
March 7, 2018: AAPS Journal
Sebastian Ueckert
Composite assessments aim to combine different aspects of a disease in a single score and are utilized in a variety of therapeutic areas. The data arising from these evaluations are inherently discrete with distinct statistical properties. This tutorial presents the framework of the item response theory (IRT) for the analysis of this data type in a pharmacometric context. The article considers both conceptual (terms and assumptions) and practical questions (modeling software, data requirements, and model building)...
January 13, 2018: CPT: Pharmacometrics & Systems Pharmacology
Kumpal Madrasi, Fang Li, Myong-Jin Kim, Snehal Samant, Stephen Voss, Theresa Kehoe, E Dennis Bashaw, Hae Young Ahn, Yaning Wang, Jeffy Florian, Stephan Schmidt, Lawrence J Lesko, Li Li
Osteoporosis is a disorder of the bones in which they are weakened to the extent that they become more prone to fracture. There are various forms of osteoporosis: some of them are induced by drugs, and others occur as a chronic progressive disorder as an individual gets older. As the median age of the population rises across the world, the chronic form of the bone disease is drawing attention as an important worldwide health issue. Developing new treatments for osteoporosis and comparing them with existing treatments are complicated processes due to current acceptance by regulatory authorities of bone mineral density (BMD) and fracture risk as clinical end points, which require clinical trials to be large, prolonged, and expensive to determine clinically significant impacts in BMD and fracture risk...
February 27, 2018: Journal of Clinical Pharmacology
Catharine C Bulik, Justin C Bader, Li Zhang, Scott A Van Wart, Christopher M Rubino, Sujata M Bhavnani, Kim L Sweeney, Paul G Ambrose
The original version of this article contained incorrect Supplementary Files. The correct Supplementary Files are published with this erratum.
February 14, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Cyrielle Dumont, Giulia Lestini, Hervé Le Nagard, France Mentré, Emmanuelle Comets, Thu Thuy Nguyen, For The Pfim Group
BACKGROUND AND OBJECTIVE: Nonlinear mixed-effect models (NLMEMs) are increasingly used for the analysis of longitudinal studies during drug development. When designing these studies, the expected Fisher information matrix (FIM) can be used instead of performing time-consuming clinical trial simulations. The function PFIM is the first tool for design evaluation and optimization that has been developed in R. In this article, we present an extended version, PFIM 4.0, which includes several new features...
March 2018: Computer Methods and Programs in Biomedicine
Anne Kümmel, Peter Bonate, Jasper Dingemanse, Andreas Krause
No abstract text is available yet for this article.
February 1, 2018: CPT: Pharmacometrics & Systems Pharmacology
Marissa F Dockendorf, Ryan C Vargo, Ferdous Gheyas, Anne S Y Chain, Manash S Chatterjee, Larissa A Wenning
Cardiovascular disease remains a significant global health burden, and development of cardiovascular drugs in the current regulatory environment often demands large and expensive cardiovascular outcome trials. Thus, the use of quantitative pharmacometric approaches which can help enable early Go/No Go decision making, ensure appropriate dose selection, and increase the likelihood of successful clinical trials, have become increasingly important to help reduce the risk of failed cardiovascular outcomes studies...
January 20, 2018: Journal of Pharmacokinetics and Pharmacodynamics
A Schmitt, L Nguyen, G Zorza, P Ferré, A Pétain
AIMS: Vinflunine is a novel tubulin-targeted inhibitor indicated as a single agent for the treatment of bladder cancers after failure of prior platinum-based therapy. Its pharmacokinetics (PK) and pharmacodynamics (PD) have been independently characterized through several phase I and phase II studies. However, no global pharmacometric analysis had been conducted yet. METHODS: Vinflunine concentrations and safety data from 18 phase I and phase II studies were used to conduct population PK and PK/PD analysis, using Nonmem...
January 17, 2018: British Journal of Clinical Pharmacology
Justin C Bader, Sujata M Bhavnani, David R Andes, Paul G Ambrose
First-line antifungal therapies are limited to azoles, polyenes and echinocandins, the former two of which are associated with high occurrences of severe treatment-emergent adverse events or frequent drug interactions. Among antifungals, echinocandins present a unique value proposition given their lower rates of toxic events as compared with azoles and polyenes. However, with the emergence of echinocandin-resistant Candida species and the fact that a pharmacometric approach to the development of anti-infective agents was not a mainstream practice at the time these agents were developed, we question whether echinocandins are being dosed optimally...
January 1, 2018: Journal of Antimicrobial Chemotherapy
V Lukyanchuk, D Kravets, D Litvinenko
In series of pharmacometrics research by determination of an optimum model of dosing is established that introduction of OKAGERM-4 in a dose of 96.8 mg/kg administered 40 minutes before the start of hypoxic damage realizes in maximum increase of estimated life expectancy of animals in hermetically sealed containers (65.57 min), ensuring a maximum effect of potential pharmacotherapeutic remedy - tartaric acid-based coordination compound of germanium with manganese. Thus, the results of pharmacometric research aimed to develop dosing regimen of OKAGERM-4 may be the base for future episodes of its pre-clinical study...
November 2017: Georgian Medical News
Koichiro Yoneyama, Christophe Schmitt, Naoki Kotani, Gallia G Levy, Ryu Kasai, Satofumi Iida, Midori Shima, Takehiko Kawanishi
BACKGROUND: Emicizumab (ACE910) is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII. In phase I-I/II studies, emicizumab reduced the bleeding frequency in patients with severe hemophilia A, regardless of the presence of factor VIII inhibitors, at once-weekly subcutaneous doses of 0.3, 1, and 3 mg/kg. METHODS: Using the phase I-I/II study data, population pharmacokinetic and repeated time-to-event (RTTE) modeling were performed to quantitatively characterize the relationship between the pharmacokinetics of emicizumab and reduction in bleeding frequency...
December 6, 2017: Clinical Pharmacokinetics
Pengyue Zhang, Heng-Yi Wu, Chien-Wei Chiang, Lei Wang, Samar Binkheder, Xueying Wang, Donglin Zeng, Sara K Quinney, Lang Li
Drug interaction is a leading cause of adverse drug events and a major obstacle for current clinical practice. Pharmacovigilance data mining, pharmacokinetic modeling, and text mining are computation and informatic tools on integrating drug interaction knowledge and generating drug interaction hypothesis. We provide a comprehensive overview of these translational biomedical informatics methodologies with related databases. We hope this review illustrates the complementary nature of these informatic approaches and facilitates the translational drug interaction research...
February 2018: CPT: Pharmacometrics & Systems Pharmacology
Pascal Schulthess, Teun M Post, James Yates, Piet H van der Graaf
Drug dosing regimen can significantly impact drug effect and, thus, the success of treatments. Nevertheless, trial and error is still the most commonly used method by conventional pharmacometric approaches to optimize dosing regimen. In this tutorial, we utilize four distinct classes of quantitative systems pharmacology models to introduce frequency-domain response analysis, a method widely used in electrical and control engineering that allows the analytical optimization of drug treatment regimen from the dynamics of the model...
November 28, 2017: CPT: Pharmacometrics & Systems Pharmacology
Elizabeth A Lakota, Justin C Bader, Christopher M Rubino
Pharmacokinetic studies and analyses can be expensive, time consuming, and labor intensive. However, it is crucial to understand that much of what happens in antimicrobial drug development, such as dose-selection and clinical study design, can be optimized with a strong understanding of the underlying pharmacokinetics of an agent. In this way, pharmacokinetics forms the bedrock of a pharmacometric approach to antimicrobial development. Thus, pharmacokinetic analyses must be considered an integral part of a drug's development strategy and studies must be planned and designed accordingly...
November 17, 2017: Current Opinion in Pharmacology
Oskar Clewe, Sebastian G Wicha, Corné P de Vogel, Jurriaan E M de Steenwinkel, Ulrika S H Simonsson
Background: Identification of pharmacodynamic interactions is not reasonable to carry out in a clinical setting for many reasons. The aim of this work was to develop a model-informed preclinical approach for prediction of clinical pharmacodynamic drug interactions in order to inform early anti-TB drug development. Methods: In vitro time-kill experiments were performed with Mycobacterium tuberculosis using rifampicin, isoniazid or ethambutol alone as well as in different combinations at clinically relevant concentrations...
November 9, 2017: Journal of Antimicrobial Chemotherapy
Yasunori Aoki, Daniel Röshammar, Bengt Hamrén, Andrew C Hooker
Population model-based (pharmacometric) approaches are widely used for the analyses of phase IIb clinical trial data to increase the accuracy of the dose selection for phase III clinical trials. On the other hand, if the analysis is based on one selected model, model selection bias can potentially spoil the accuracy of the dose selection process. In this paper, four methods that assume a number of pre-defined model structure candidates, for example a set of dose-response shape functions, and then combine or select those candidate models are introduced...
December 2017: Journal of Pharmacokinetics and Pharmacodynamics
Silvia Maria Lavezzi, Elisa Borella, Letizia Carrara, Giuseppe De Nicolao, Paolo Magni, Italo Poggesi
Drug attrition in oncology clinical development is higher than other therapeutic areas. In this context, pharmacometric modeling represents a useful tool to explore drug efficacy in earlier phases of clinical development, anticipating overall survival using quantitative model-based metrics. Furthermore, modeling approaches can be used to characterize earlier the safety and tolerability profile of drug candidates, and, thus, the risk-benefit ratio and the therapeutic index, supporting the design of optimal treatment regimens and accelerating the whole process of clinical drug development...
October 3, 2017: Expert Opinion on Drug Discovery
(no author information available yet)
No abstract text is available yet for this article.
October 2017: Journal of Pharmacokinetics and Pharmacodynamics
Brenda Cirincione, Navin Goyal, Rene Bruno
No abstract text is available yet for this article.
October 2017: Journal of Pharmacokinetics and Pharmacodynamics
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