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Journal of Pharmacokinetics and Pharmacodynamics

Felix Held, Edmund Hoppe, Marija Cvijovic, Mats Jirstrand, Johan Gabrielsson
A mechanism-based biomarker model of TNFα -response, including different external provocations of LPS challenge and test compound intervention, was developed. The model contained system properties (such as kt , kout ), challenge characteristics (such as ks , kLPS , Km, LPS , Smax , SC50 ) and test-compound-related parameters (Imax , IC50 ). The exposure to test compound was modelled by means of first-order input and Michaelis-Menten type of nonlinear elimination. Test compound potency was estimated to 20 nM with a 70% partial reduction in TNFα -response at the highest dose of 30 mg·kg-1 ...
February 18, 2019: Journal of Pharmacokinetics and Pharmacodynamics
Vivaswath S Ayyar, Wojciech Krzyzanski, William J Jusko
Rhythmicity in baseline responses over a 24-h period for an indirect pharmacological effect R(t) can arise from either a periodic time-dependent input rate [Formula: see text] or a periodic time-dependent loss constant [Formula: see text]. If either [Formula: see text] or [Formula: see text] follows some nonstationary biological rhythm (e.g., circadian), then the response R(t) also displays a periodic behavior. Indirect response models assuming time-dependent input rates [Formula: see text] have been utilized to capture drug effects on various physiological responses such as hormone suppression, immune cell trafficking, and gene expression in tissues...
January 29, 2019: Journal of Pharmacokinetics and Pharmacodynamics
Felix Held, Carl Ekstrand, Marija Cvijovic, Johan Gabrielsson, Mats Jirstrand
Cortisol is a steroid hormone relevant to immune function in horses and other species and shows a circadian rhythm. The glucocorticoid dexamethasone suppresses cortisol in horses. Pituitary pars intermedia dysfunction (PPID) is a disease in which the cortisol suppression mechanism through dexamethasone is challenged. Overnight dexamethasone suppression test (DST) protocols are used to test the functioning of this mechanism and to establish a diagnosis for PPID. However, existing DST protocols have been recognized to perform poorly in previous experimental studies, often indicating presence of PPID in healthy horses...
January 23, 2019: Journal of Pharmacokinetics and Pharmacodynamics
Hongmei Xu, Xiao Tong, Ganesh Mugundu, Martin L Scott, Carl Cook, Cecilia Arfvidsson, Elizabeth Pease, Diansong Zhou, Paul Lyne, Nidal Al-Huniti
Danvatirsen is a Generation 2.5 antisense oligonucleotide under clinical development. Population PK modelling was conducted using data from 3 available danvatirsen Phase I/II studies in oncology patients to investigate the impact of flat dosing on exposure compared to ideal body weight-based dosing. A total of 126 patients who received danvatirsen doses ranging from 1 to 4 mg/kg as monotherapy or in combination with durvalumab, most at 3 mg/kg (n = 70), was used in the danvatirsen population PK analysis...
January 19, 2019: Journal of Pharmacokinetics and Pharmacodynamics
Wojciech Krzyzanski
In many models of pharmacodynamic systems with delays, a delay of an input is introduced by means of the convolution with the gamma distribution. An approximation of the convolution integral of bound functions based on a system of ordinary differential equations that utilizes properties of the binomial series has been introduced. The approximation converges uniformly on every compact time interval and an estimate of the approximation error has been found [Formula: see text] where [Formula: see text] is the number of differential equations and [Formula: see text] is the shape parameter of the gamma distribution...
January 7, 2019: Journal of Pharmacokinetics and Pharmacodynamics
Leonid Khinkis, Milburn Crotzer
Since simulation studies are widely used in pharmacokinetics, it is necessary to ascertain their validity. An important, well-documented, concern that may negatively impact the validity of estimated parameters in pharmacokinetic models is existence of multiple minima of the criterion used in estimation. A presence of multiple minima causes instability of the estimates, dependence of the parameter estimates on the initial values, and bimodal (or, generally, multimodal) distributions of the estimated parameters...
January 3, 2019: Journal of Pharmacokinetics and Pharmacodynamics
Nicola Melillo, Leon Aarons, Paolo Magni, Adam S Darwich
Regulatory agencies have a strong interest in sensitivity analysis for the evaluation of physiologically-based pharmacokinetic (PBPK) models used in pharmaceutical research and drug development and regulatory submissions. One of the applications of PBPK is the prediction of fraction absorbed and bioavailability for drugs following oral administration. In this context, we performed a variance based global sensitivity analysis (GSA) on in-house PBPK models for drug absorption, with the aim of identifying key parameters that influence the predictions of the fraction absorbed and the bioavailability for neutral, acidic and basic compounds...
December 14, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Silvia Maria Lavezzi, Enrica Mezzalana, Stefano Zamuner, Giuseppe De Nicolao, Peiming Ma, Monica Simeoni
The aim of the present study was to evaluate model identifiability when minimal physiologically-based pharmacokinetic (mPBPK) models are integrated with target mediated drug disposition (TMDD) models in the tissue compartment. Three quasi-steady-state (QSS) approximations of TMDD dynamics were explored: on (a) antibody-target complex, (b) free target, and (c) free antibody concentrations in tissue. The effects of the QSS approximations were assessed via simulations, taking as reference the mPBPK-TMDD model with no simplifications...
December 2018: Journal of Pharmacokinetics and Pharmacodynamics
Spencer Frank, Abdulrahman Jbaily, Ling Hinshaw, Rita Basu, Ananda Basu, Andrew J Szeri
Our objective is to develop a physiology-based model of insulin kinetics to understand how exercise alters insulin concentrations in those with type 1 diabetes (T1D). We reveal the relationship between the insulin absorption rate ([Formula: see text]) from subcutaneous tissue, the insulin delivery rate ([Formula: see text]) to skeletal muscle, and two physiological parameters that characterize the tissue: the perfusion rate (Q) and the capillary permeability surface area (PS), both of which increase during exercise because of capillary recruitment...
December 2018: Journal of Pharmacokinetics and Pharmacodynamics
Konstantinos Biliouris, Ivan Nestorov, Himanshu Naik, David Dai, Guangqing Xiao, Qin Wang, Alex Pellerin, Dania Rabah, Lawrence J Lesko, Mirjam N Trame
BIIB059 is a novel humanized monoclonal antibody (mAb) that is currently under development for the treatment of Systemic Lupus Erythematosus and Cutaneous Lupus Erythematosus. BIIB059 is targeted against the blood dendritic cell antigen 2 (BDCA2), a receptor exclusively expressed on the surface of plasmacytoid dendritic cells (pDCs). Herein, we utilized pre-clinical pharmacokinetic (PK) and pharmacodynamic (PD) data to develop a non-human primate (NHP) model and to address whether the NHP model can be successfully scaled to predict the human PK/PD...
December 2018: Journal of Pharmacokinetics and Pharmacodynamics
Chuanpu Hu, Omoniyi J Adedokun, Liping Zhang, Amarnath Sharma, Honghui Zhou
Accurate characterization of exposure-response relationship of clinical endpoints is important in drug development to identify optimal dose regimens. Endpoints with ≥ 10 ordered categories are typically analyzed as continuous. This manuscript aims to show circumstances where it is advantageous to analyze such data as ordered categorical. The results of continuous and categorical analyses are compared in a latent-variable based Indirect Response modeling framework for the longitudinal modeling of Mayo scores, ranging from 0 to 12, which is commonly used as a composite endpoint to measure the severity of ulcerative colitis (UC)...
December 2018: Journal of Pharmacokinetics and Pharmacodynamics
Robin Michelet, Jan Van Bocxlaer, Karel Allegaert, An Vermeulen
The project SAFEPEDRUG aims to provide guidelines for drug research in children, based on bottom-up and top-down approaches. Propofol, one of the studied model compounds, was selected because it is extensively metabolized in liver and kidney, with an important role for the glucuronidation pathway. Besides, being a lipophilic molecule, it is distributed into fat tissues, from where it redistributes into the systemic circulation. In the past, both bottom-up (Physiologically based pharmacokinetic, PBPK) and top-down approaches (population pharmacokinetic, popPK) were applied to describe its pharmacokinetics (PK)...
December 2018: Journal of Pharmacokinetics and Pharmacodynamics
Yeshitila Gebremichael, Gezim Lahu, Majid Vakilynejad, K Melissa Hallow
Multiple classes of antihypertensive drugs inhibit components of the renin-angiotensin-aldosterone system (RAAS). The primary physiological effector of the RAAS is angiotensin II (AngII) bound to the AT1 receptor (AT1-bound AngII). There is a strong non-linear feedback from AT1-bound AngII on renin secretion. Since AT1-bound AngII is not readily measured experimentally, plasma renin concentration (PRC) and/or activity (PRA) are typically measured to indicate RAAS suppression. We investigated the RAAS suppression of imarikiren hydrochloride (TAK-272; SCO-272), a direct renin inhibitor currently under clinical development...
November 16, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Zheng Liu, Aly Diana, Christine Slater, Thomas Preston, Rosalind S Gibson, Lisa Houghton, Stephen B Duffull
The World Health Organization recommends exclusive breastfeeding (EBF) for the first 6 months after birth. The deuterium oxide dose-to-the-mother (DTM) technique is used to distinguish EBF based on a cut-off (< 25 g/day) of water intake from sources other than breastmilk. This value is based on a theoretical threshold and has not been verified in field studies. The aim of this study was to estimate the water intake cut-off value that can be used to define EBF practice. One hundred and twenty-one healthy infants, aged 2...
November 14, 2018: Journal of Pharmacokinetics and Pharmacodynamics
(no author information available yet)
No abstract text is available yet for this article.
October 2018: Journal of Pharmacokinetics and Pharmacodynamics
Wilhelmus E A de Witte, Vivi Rottschäfer, Meindert Danhof, Piet H van der Graaf, Lambertus A Peletier, Elizabeth C M de Lange
The original version of this article was published open access. Unfortunately, due to a technical issue, the copyright holder name in the online version (HTML and XML) is incorrectly published as "Springer Science+Business Media, LLC, part of Springer Nature 2018". Instead, it should be "The Author(s) 2018".
October 2018: Journal of Pharmacokinetics and Pharmacodynamics
Xu Zhu, Sheryl Trueman, Robert M Straubinger, William J Jusko
The anticancer effects of combined gemcitabine and birinapant were demonstrated as synergistic in PANC-1 cells in vitro. In this study, pharmacokinetic information derived from experiments and the literature was utilized to develop full physiologically-based pharmacokinetic (PBPK) models that characterize individual drugs. The predicted intra-tumor drug concentrations were used as the driving force within a linked PBPK/PD model for treatment-mediated changes in tumor volume in a xenograft mouse model. The efficacy of the drug combination in vivo was evaluated mathematically as exhibiting additivity...
October 2018: Journal of Pharmacokinetics and Pharmacodynamics
Andrijana Radivojevic, Brian Corrigan, Nicholas Downie, Robert Fox, Jill Fiedler-Kelly, Huan Liu, Murad Melhem, David Radke, Peter Schaefer, Jing Su, Maciej J Swat, Nathan S Teuscher, Neelima Thanneer, Alice Zong, Justin J Wilkins
No abstract text is available yet for this article.
October 2018: Journal of Pharmacokinetics and Pharmacodynamics
Dongwoo Chae, Kyungsoo Park
This study developed an integrated model of severity scores of migraine headache and the incidence of nausea, photophobia, and phonophobia to predict the natural time course of migraine symptoms, which are likely to occur by a common disease progression mechanism. Data were acquired from two phase 3 clinical trials conducted during the development of eletriptan. Only the placebo arm was used for analysis. A conventional proportional odds model was compared with an item response theory (IRT) based approach. Results suggested that the IRT based approach led to a better model fit, successfully revealing the difference in relief rates among different symptoms, which was the fastest in phonophobia and the slowest in headache...
October 2018: Journal of Pharmacokinetics and Pharmacodynamics
Chuanpu Hu, Yan Xu, Yanli Zhuang, Benjamin Hsu, Amarnath Sharma, Zhenhua Xu, Liping Zhang, Honghui Zhou
Exposure-response modeling is important to optimize dose and dosing regimen in clinical drug development. The joint modeling of multiple endpoints is made possible in part by recent progress in latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript presents the results of joint modeling of continuous and ordered categorical endpoints in the latent variable IDR modeling framework through the sharing of model parameters, with an application to the exposure-response modeling of sirukumab...
October 2018: Journal of Pharmacokinetics and Pharmacodynamics
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