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Journal of Pharmacokinetics and Pharmacodynamics

Chuanpu Hu, Zhenling Yao, Yang Chen, Bruce Randazzo, Liping Zhang, Zhenhua Xu, Amarnath Sharma, Honghui Zhou
Guselkumab, a human IgG1 monoclonal antibody that blocks interleukin-23, has been evaluated in one Phase 2 and two Phase 3 trials in patients with moderate-to-severe psoriasis, in which disease severity was assessed using Psoriasis Area and Severity Index (PASI) and Investigator's Global Assessment (IGA) scores. Through the application of landmark and longitudinal exposure-response (E-R) modeling analyses, we sought to predict the guselkumab dose-response (D-R) relationship using data from 1459 patients who participated in these trials...
March 16, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Barbara Wiśniowska, Sebastian Polak
The current study is an example of drug-disease interaction modeling where a drug induces a condition which can affect the pharmacodynamics of other concomitantly taken drugs. The electrophysiological effects of hypokaliemia and heart rate changes induced by the antiasthmatic drugs were simulated with the use of the cardiac safety simulator. Biophysically detailed model of the human cardiac physiology-ten Tusscher ventricular cardiomyocyte cell model-was employed to generate pseudo-ECG signals and QTc intervals for 44 patients from four clinical studies...
March 15, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Sebastian Polak, Klaus Romero, Alexander Berg, Nikunjkumar Patel, Masoud Jamei, David Hermann, Debra Hanna
Cardiotoxicity is among the top drug safety concerns, and is of specific interest in tuberculosis, where this is a known or potential adverse event of current and emerging treatment regimens. As there is a need for a tool, beyond the QT interval, to quantify cardiotoxicity early in drug development, an empirical decision tree based classifier was developed to predict the risk of Torsades de pointes (TdP). The cardiac risk algorithm was developed using pseudo-electrocardiogram (ECG) outputs derived from cardiac myocyte electromechanical model simulations of increasing concentrations of 96 reference compounds which represented a range of clinical TdP risk...
March 8, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Tanaya Vaidya, Jeff Kamta, Maher Chaar, Anusha Ande, Sihem Ait-Oudhia
Tyrosine kinase inhibitors (TKIs) are targeted therapies rapidly becoming favored over conventional cytotoxic chemotherapeutics. Our study investigates two FDA approved TKIs, DASATINIB; indicated for IMATINIB-refractory chronic myeloid leukemia, and SORAFENIB; indicated for hepatocellular carcinoma and advanced renal cell carcinoma. Limited but crucial evidence suggests that these agents can have cardiotoxic side effects ranging from hypertension to heart failure. A greater understanding of the underlying mechanisms of this cardiotoxicity are needed as concerns grow and the capacity to anticipate them is lacking...
February 14, 2018: Journal of Pharmacokinetics and Pharmacodynamics
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
Wojciech Krzyzanski, Shuhua Hu, Michael Dunlavey
The distributed delay model has been introduced that replaces the transit compartments in the classic model of chemotherapy-induced myelosuppression with a convolution integral. The maturation of granulocyte precursors in the bone marrow is described by the gamma probability density function with the shape parameter (ν). If ν is a positive integer, the distributed delay model coincides with the classic model with ν transit compartments. The purpose of this work was to evaluate performance of the distributed delay model with particular focus on model deterministic identifiability in the presence of the shape parameter...
February 12, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Samantha H Dallefeld, Andrew M Atz, Ram Yogev, Janice E Sullivan, Amira Al-Uzri, Susan R Mendley, Matthew Laughon, Christoph P Hornik, Chiara Melloni, Barrie Harper, Andrew Lewandowski, Jeff Mitchell, Huali Wu, Thomas P Green, Michael Cohen-Wolkowiez
Amiodarone is a first-line antiarrhythmic for life-threatening ventricular fibrillation or ventricular tachycardia in children, yet little is known about its pharmacokinetics (PK) in this population. We developed a population PK (PopPK) model using samples collected via an opportunistic study design of children receiving amiodarone per standard of care supplemented by amiodarone PK data from the literature. Both study data and literature data were predominantly from infants < 2 years old, so our analysis was restricted to this group...
February 12, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Aurelia H M de Vries Schultink, Annelies H Boekhout, Jourik A Gietema, Artur M Burylo, Thomas P C Dorlo, J G Coen van Hasselt, Jan H M Schellens, Alwin D R Huitema
Trastuzumab is associated with cardiotoxicity, manifesting as a decrease of the left-ventricular ejection fraction (LVEF). Administration of anthracyclines prior to trastuzumab increases risk of cardiotoxicity. High-sensitive troponin T and N-terminal-pro-brain natriuretic peptide (NT-proBNP) are molecular markers that may allow earlier detection of drug-induced cardiotoxicity. In this analysis we aimed to quantify the kinetics and exposure-response relationships of LVEF, troponin T and NT-proBNP measurements, in patients receiving anthracycline and trastuzumab...
February 10, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Dwaipayan Mukherjee, Jiuhong Zha, Rajeev M Menon, Mohamad Shebley
Amlodipine, a commonly prescribed anti-hypertensive drug, shows increased systemic exposure with cytochrome P450 (CYP) 3A inhibitors. Ritonavir (RTV) is a potent mechanism-based and reversible CYP3A inhibitor and moderate inducer that is used as a pharmacokinetic enhancer in several antiviral treatment regimens. Drug-drug interaction (DDI) between RTV and amlodipine is due to mixed inhibition and induction of CYP3A4, which is challenging to predict without a mechanistic model that accounts for the complexity of both mechanisms occurring simultaneously...
February 9, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Megerle L Scherholz, James Forder, Ioannis P Androulakis
Parameter sensitivity and uncertainty analysis for physiologically based pharmacokinetic (PBPK) models are becoming an important consideration for regulatory submissions, requiring further evaluation to establish the need for global sensitivity analysis. To demonstrate the benefits of an extensive analysis, global sensitivity was implemented for the GastroPlus™ model, a well-known commercially available platform, using four example drugs: acetaminophen, risperidone, atenolol, and furosemide. The capabilities of GastroPlus were expanded by developing an integrated framework to automate the GastroPlus graphical user interface with AutoIt and for execution of the sensitivity analysis in MATLAB®...
February 8, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Dhaval K Shah, Frank Loganzo, Nahor Haddish-Berhane, Sylvia Musto, Hallie S Wald, Frank Barletta, Judy Lucas, Tracey Clark, Steve Hansel, Alison Betts
The objective of this manuscript was to establish in vitro-in vivo correlation (IVIVC) between the in vitro efficacy and in vivo efficacy of antibody drug conjugates (ADCs), using a PK/PD modeling approach. Nineteen different ADCs were used to develop IVIVC. In vitro efficacy of ADCs was evaluated using a kinetic cell cytotoxicity assay. The cytotoxicity data obtained from in vitro studies was characterized using a novel mathematical model, parameter estimates from which were used to derive an in vitro efficacy matrix for each ADC, termed as 'in vitro tumor static concentration' (TSCin vitro )...
February 8, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Neil D Evans, S Y Amy Cheung, James W T Yates
Structural identifiability is an often overlooked, but essential, prerequisite to the experiment design stage. The application of structural identifiability analysis to models of myelosuppression is used to demonstrate the importance of its considerations. It is shown that, under certain assumptions, these models are structurally identifiable and so drug and system specific parameters can truly be separated. Further it is shown via a meta-analysis of the literature that because of this the reported system parameter estimates for the "Friberg" or "Uppsala" model are consistent in the literature...
February 2, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Shuhua Hu, Michael Dunlavey, Serge Guzy, Nathan Teuscher
A distributed delay approach was proposed in this paper to model delayed outcomes in pharmacokinetics and pharmacodynamics studies. This approach was shown to be general enough to incorporate a wide array of pharmacokinetic and pharmacodynamic models as special cases including transit compartment models, effect compartment models, typical absorption models (either zero-order or first-order absorption), and a number of atypical (or irregular) absorption models (e.g., parallel first-order, mixed first-order and zero-order, inverse Gaussian, and Weibull absorption models)...
January 24, 2018: Journal of Pharmacokinetics and Pharmacodynamics
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
Christine Garnett, Peter L Bonate, Qianyu Dang, Georg Ferber, Dalong Huang, Jiang Liu, Devan Mehrotra, Steve Riley, Philip Sager, Christoffer Tornoe, Yaning Wang
The original version of this article unfortunately contained an error in Equation 1 under the section "Pre-specified linear mixed effects model". The correct equation has given below.
January 12, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Gilbert Koch, Johannes Schropp
Indirect response (IDR) models are probably the most frequently applied tools relating the effect of a signal to a baseline response. A response modeled by such a classical IDR model will always return monotonously to its baseline after drug administration. We extend IDR models with a delay process, i.e. a retarded response state, that leads to oscillating response behavior. First, IDR models with a first-order production and second-order loss term based on the famous logistic equation are constructed. Second, a delay process similar to the delayed logistic equation is included...
January 8, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Peter Bloomingdale, Van Anh Nguyen, Jin Niu, Donald E Mager
Quantitative systems pharmacology (QSP) is an emerging discipline that aims to discover how drugs modulate the dynamics of biological components in molecular and cellular networks and the impact of those perturbations on human pathophysiology. The integration of systems-based experimental and computational approaches is required to facilitate the advancement of this field. QSP models typically consist of a series of ordinary differential equations (ODE). However, this mathematical framework requires extensive knowledge of parameters pertaining to biological processes, which is often unavailable...
January 6, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Iraj Hosseini, Anita Gajjala, Daniela Bumbaca Yadav, Siddharth Sukumaran, Saroja Ramanujan, Ricardo Paxson, Kapil Gadkar
Modeling and simulation (M&S) is increasingly used in drug development to characterize pharmacokinetic-pharmacodynamic (PKPD) relationships and support various efforts such as target feasibility assessment, molecule selection, human PK projection, and preclinical and clinical dose and schedule determination. While model development typically require mathematical modeling expertise, model exploration and simulations could in many cases be performed by scientists in various disciplines to support the design, analysis and interpretation of experimental studies...
January 4, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Wojciech Krzyzanski, J G Coen van Hasselt
No abstract text is available yet for this article.
January 3, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Piotr Smuszkiewicz, Paweł Wiczling, Justyna Ber, Justyna Warzybok, Tomasz Małkiewicz, Jan Matysiak, Agnieszka Klupczyńska, Iwona Trojanowska, Zenon Kokot, Edmund Grześkowiak, Wojciech Krzyzanski, Agnieszka Bienert
Dexmedetomidine (DEX) is a fairly new alfa2-agonist which has been increasingly used in recent years for analgosedation, mostly because it offers a unique ability of providing both moderate level of sedation and analgesia without respiratory depression. Despite of many papers published, there are still only a few concerning the PK of the drug given as long-term infusion in ICU patients. The aim of this work was to characterize the population pharmacokinetics of dexmedetomidine and to investigate the potential benefits of individualization of drug dosing based on patient characteristics in the heterogeneous group of medical and surgical patients staying in intensive care unit...
December 30, 2017: Journal of Pharmacokinetics and Pharmacodynamics
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