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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
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...
November 10, 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...
November 3, 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...
October 30, 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)...
October 30, 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)...
October 8, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Peter L Bonate, Tianli Wang, Paul Passier, Wilhelmina Bagchus, Howard Burt, Christian Lüpfert, Nada Abla, Jana Kovac, Jennifer Keiser
L-praziquantel (PZQ) pharmacokinetic data were analyzed from two relative bioavailability Phase 1 studies in adult, healthy subjects with two new oral dispersion tablet (ODT) formulations of L-PZQ administered under various combinations of co-administration with food, water, and/or crushing. Linear mixed effects models adequately characterized the noncompartmental estimates of the pharmacokinetic profiles in both studies. Dose, food, and formulation were found to significantly affect L-PZQ exposure in both studies...
September 14, 2018: Journal of Pharmacokinetics and Pharmacodynamics
(no author information available yet)
No abstract text is available yet for this article.
September 10, 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
Zofia Tylutki, Aleksander Mendyk, Sebastian Polak
The physiologically based pharmacokinetic (PBPK) models allow for predictive assessment of variability in population of interest. One of the future application of PBPK modeling is in the field of precision dosing and personalized medicine. The aim of the study was to develop PBPK model for amitriptyline given orally, predict the variability of cardiac concentrations of amitriptyline and its main metabolite-nortriptyline in populations as well as individuals, and simulate the influence of those xenobiotics in therapeutic and supratherapeutic concentrations on human electrophysiology...
October 2018: Journal of Pharmacokinetics and Pharmacodynamics
Soujanya Sunkaraneni, Elizabeth Ludwig, Jill Fiedler-Kelly, Seth Hopkins, Gerald Galluppi, David Blum
Modeling and simulations were used to support body weight-based dose selection for eslicarbazepine acetate (ESL) in pediatric subjects aged 4-17 years with partial-onset seizures. A one-compartment pediatric population pharmacokinetic model with formulation-specific first-order absorption, first-order elimination, and weight-based allometric scaling of clearance and distribution volume was developed with PK data from subjects 2-18 years of age treated with ESL 5-30 mg/kg/day. Covariate analysis was performed to quantify the effects of key demographic and clinical covariates (including body weight and concomitant use of carbamazepine, levetiracetam, and phenobarbital-like antiepileptic drugs [AEDs]) on variability in PK parameters...
August 2018: Journal of Pharmacokinetics and Pharmacodynamics
A Brekkan, S Jönsson, M O Karlsson, A C Hooker
Monoclonal antibodies against soluble targets are often rich and include the sampling of multiple analytes over a lengthy period of time. Predictive models built on data obtained in such studies can be useful in all drug development phases. If adequate model predictions can be maintained with a reduced design (e.g. fewer samples or shorter duration) the use of such designs may be advocated. The effect of reducing and optimizing a rich design based on a published study for Omalizumab (OMA) was evaluated as an example...
August 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
Drug-target binding kinetics (as determined by association and dissociation rate constants, kon and koff ) can be an important determinant of the kinetics of drug action. However, the effect compartment model is used most frequently instead of a target binding model to describe hysteresis. Here we investigate when the drug-target binding model should be used in lieu of the effect compartment model. The utility of the effect compartment (EC), the target binding kinetics (TB) and the combined effect compartment-target binding kinetics (EC-TB) model were tested on either plasma (ECPL , TBPL and EC-TBPL ) or brain extracellular fluid (ECF) (ECECF , TBECF and EC-TBECF ) morphine concentrations and EEG amplitude in rats...
August 2018: Journal of Pharmacokinetics and Pharmacodynamics
Anusha Ande, Maher Chaar, Sihem Ait-Oudhia
Dysregulation of mTOR pathway is common in hepatocellular carcinoma (HCC). A translational quantitative systems pharmacology (QSP), pharmacokinetic (PK), and pharmacodynamic (PD) model dissecting the circuitry of this pathway was developed to predict HCC patients' response to everolimus, an mTOR inhibitor. The time course of key signaling proteins in the mTOR pathway, HCC cells viability, tumor volume (TV) and everolimus plasma and tumor concentrations in xenograft mice, clinical PK of everolimus and progression free survival (PFS) in placebo and everolimus-treated patients were extracted from literature...
August 2018: Journal of Pharmacokinetics and Pharmacodynamics
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