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CPT: Pharmacometrics & Systems Pharmacology

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https://www.readbyqxmd.com/read/29115052/dose-selection-based-on-modeling-and-simulation-for-rivipansel-in-pediatric-patients-aged-6-to-11-years-with-sickle-cell-disease
#1
Brinda K Tammara, Lutz O Harnisch
This modeling and simulation exercise aimed to provide dosing recommendations for rivipansel phase 3 studies in children aged 6 to 11 years with sickle cell disease (SCD). Pharmacokinetic data from 109 patients aged 12 to 51 years who received rivipansel (2-40 mg/kg) in previous studies (3 phase 1, one phase 2) were integrated to build a 3-compartmental simulation model. Renal clearance simulations across the age range accounted for renal function development and postulated hyperfiltration in SCD. Simulated demographic distributions for the pediatric SCD population were used to predict concentration-time profiles from 3 dosing regimens, which were then compared against efficacious average steady-state concentrations observed in phase 2...
November 8, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29068158/development-of-an-adult-physiologically-based-pharmacokinetic-model-of-solithromycin-in-plasma-and-epithelial-lining-fluid
#2
Sara N Salerno, Andrea Edginton, Michael Cohen-Wolkowiez, Christoph P Hornik, Kevin M Watt, Brian D Jamieson, Daniel Gonzalez
Solithromycin is a fluoroketolide antibiotic under investigation for community-acquired bacterial pneumonia (CABP). We developed a whole-body physiologically based pharmacokinetic (PBPK) model for solithromycin in adults using PK-Sim and MoBi version 6.2, which incorporated time-dependent CYP3A4 auto-inhibition. The model was developed and evaluated using plasma and epithelial lining fluid (ELF) concentration data from 100 healthy subjects and 22 patients with CABP (1,966 plasma, 30 ELF samples). We performed population simulations and calculated the number of observations falling outside the 90% prediction interval...
October 25, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29064165/regarding-lactation-status-and-studies-of-pyrimethamine-pharmacokinetics-in-pregnancy
#3
LETTER
Sam Salman, Timothy M E Davis
No abstract text is available yet for this article.
October 24, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29052341/response-to-lactation-status-and-studies-of-pyrimethamine-pharmacokinetics-in-pregnancy
#4
LETTER
Miné de Kock, Joel Tarning, Karen I Barnes, Paolo Denti
No abstract text is available yet for this article.
October 20, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29045072/cell-signaling-model-connects-vorinostat-pharmacokinetics-and-tumor-growth-response-in-multiple-myeloma-xenografts
#5
Charvi Nanavati, Donna Ruszaj, Donald E Mager
Multiple myeloma is a fatal hematological malignancy with high rates of drug resistance and relapse. Vorinostat, a histone deacetylase inhibitor, has shown promise in enhancing efficacy when combined with current myeloma therapies. In this study, temporal changes of critical proteins and cell proliferation were measured in myeloma cells exposed to vorinostat. A model linking biomarker dynamics to cell proliferation was developed that captured vorinostat effects on signal transduction and cell viability. The model structure and parameters were fixed to describe tumor dynamics in vivo, and tumor-specific growth and death rate parameters were estimated...
October 17, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29024493/pharmacokinetics-and-pharmacodynamics-of-meloxicam-in-east-asian-populations-the-role-of-ethnicity-on-drug-response
#6
T Aoyama, Y Ishida, M Kaneko, A Miyamoto, Y Saito, M Tohkin, S Kawai, Y Matsumoto
We aimed to reanalyze the differences in the pharmacokinetics (PKs) of meloxicam in East Asian populations based on a population approach using previously published data and to investigate the factors found in population pharmacokinetic (PK) analysis that affect the pharmacodynamics (PDs) of meloxicam. Population PK analysis was performed in 119 healthy male subjects (30 Japanese, 30 Chinese, 29 Korean, and 30 Caucasian) under strictly controlled trial conditions with regulated meals and a single lot of the drug...
October 12, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28960826/model-based-interspecies-scaling-of-glucose-homeostasis
#7
Oskar Alskär, Mats O Karlsson, Maria C Kjellsson
Being able to scale preclinical pharmacodynamic response to clinical would be beneficial in drug development. In this work, the integrated glucose insulin (IGI) model, developed on clinical intravenous glucose tolerance test (IVGTT) data, describing dynamic glucose and insulin concentrations during glucose tolerance tests, was scaled to describe data from similar tests performed in healthy rats, mice, dogs, pigs, and humans. Several approaches to scaling the dynamic glucose and insulin were investigated. The theoretical allometric exponents of 0...
September 28, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28941225/systems-pharmacology-model-of-gastrointestinal-damage-predicts-species-differences-and-optimizes-clinical-dosing-schedules
#8
Harish Shankaran, Anna Cronin, Jen Barnes, Pradeep Sharma, John Tolsma, Paul Jasper, Jerome T Mettetal
Gastrointestinal (GI) adverse events (AE) are frequently dose limiting for oncology agents, requiring extensive clinical testing of alternative schedules to identify optimal dosing regimens. Here we develop a translational mathematical model to predict these clinical AEs starting from preclinical GI toxicity data. The model structure incorporates known biology and includes stem cells, daughter cells and enterocytes. Published data including cellular numbers and division times informed the system parameters for human and rat...
September 22, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28941007/leveraging-population-based-clinical-quantitative-phenotyping-for-drug-repositioning
#9
Adam S Brown, Danielle Rasooly, Chirag J Patel
Computational drug repositioning methods can scalably nominate approved drugs for new diseases, with reduced risk of unforeseen side effects. The majority of methods eschew individual-level phenotypes despite the promise of biomarker-driven repositioning. In this study, we propose a framework for discovering serendipitous interactions between drugs and routine clinical phenotypes in cross-sectional observational studies. Key to our strategy is the use of a healthy and non-diabetic population derived from the National Health and Nutrition Examination Survey, mitigating risk for confounding by indication...
September 22, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28925077/network-wide-screen-identifies-variation-of-novel-precise-on-module-targets-using-conformational-modudaoism
#10
Bing Li, Jun Liu, Yanan Yu, Pengqian Wang, Yingying Zhang, Xumin Ni, Qiong Liu, Xiaoxu Zhang, Zhong Wang, Yongyan Wang
Modular targeting is promising in drug research at network level, but it's challenging to quantificationally identify the precise On-modules. Based on a proposed Modudaoism (MD), we defined conserved MD (MDc) and varied MD (MDv) to quantitatively evaluate the conformational and energy variations of modules, and thereby identify the conserved and discrepant allosteric modules. Compared with the Zsummary , MDc/MDv got an optimized result of module preserved ratio and modular structure. In mice anti-ischemic networks, 3, 5, and 1 conserved allosteric modules as well as 4, 1, and 3 On-modules of baicalin (BA), jasminoidin (JA), and ursodeoxycholic acid (UA) were identified by MDc and MDv, 5 unique allosteric modules and their characteristic actions were revealed...
September 19, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28925064/improving-realism-in-clinical-trial-simulations-via-real-world-data
#11
EDITORIAL
Holly Kimko, Kwan Lee
Simulation validity depends on how well sampling distributions used reflect real-patient characteristics, such as drug adherence, disease progression, and pharmacologic handling in the body. We challenge the current use of growth charts from nondisease-specific pediatrics in simulations for drug development. Complementary use of data from clinical trials and the real-world is expected to achieve a more realistic representation of clinical outcomes for decisions in drug development, regulatory approval, and health technology assessment...
September 19, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28891251/dose-exposure-response-modeling-to-support-dosing-recommendation-for-phase-3-development-of-baricitinib-in-patients-with-rheumatoid-arthritis
#12
X Zhang, L Chua, C Ernest, W Macias, T Rooney, L S Tham
Baricitinib is an oral inhibitor of Janus kinases (JAK), selective for JAK1 and 2. It demonstrated dose-dependent efficacy in patients with moderate-to-severe rheumatoid arthritis in a Phase 2b study up to 24 weeks. Population pharmacokinetic/pharmacodynamic models were developed to characterize concentration-time profiles and dose/exposure-response relationships for the key efficacy (proportion of patients achieving American College of Rheumatology 20%, 50%, or 70% response rate) and safety endpoints (incidence of anemia) for the Phase 2b study...
September 11, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28891201/predicting-drug-concentration-time-profiles-in-multiple-cns-compartments-using-a-comprehensive-physiologically-based-pharmacokinetic-model
#13
Yumi Yamamoto, Pyry A Välitalo, Dymphy R Huntjens, Johannes H Proost, An Vermeulen, Walter Krauwinkel, Margot W Beukers, Dirk-Jan van den Berg, Robin Hartman, Yin Cheong Wong, Meindert Danhof, John G C van Hasselt, Elizabeth C M de Lange
Drug development targeting the central nervous system (CNS) is challenging due to poor predictability of drug concentrations in various CNS compartments. We developed a generic physiologically based pharmacokinetic (PBPK) model for prediction of drug concentrations in physiologically relevant CNS compartments. System-specific and drug-specific model parameters were derived from literature and in silico predictions. The model was validated using detailed concentration-time profiles from 10 drugs in rat plasma, brain extracellular fluid, 2 cerebrospinal fluid sites, and total brain tissue...
September 11, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29076294/corrigendum-population-pharmacokinetics-of-selumetinib-and-its-metabolite-n-desmethyl-selumetinib-in-adult-patients-with-advanced-solid-tumors-and-children-with-low-grade-gliomas
#14
(no author information available yet)
No abstract text is available yet for this article.
October 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28960845/simultaneous-modeling-of-biomarker-and-toxicity-response-predicted-optimal-regimen-of-guadecitabine-sgi-110-in-myeloid-malignancies
#15
Cong Xu, Timothy K Goggin, Xiang-Yao Su, Pietro Taverna, Aram Oganesian, James N Lowder, Mohammad Azab, Hagop Kantarjian
Guadecitabine (SGI-110) is a novel next-generation hypomethylating agent (HMA) administered as s.c. injection with extended decitabine exposure. Dose/exposure-response analyses of longitudinal measures of long interspersed nucleotide element-1 (LINE-1) methylation and absolute neutrophil counts (ANC) pooled from 79 and 369 patients in 2 phase I/II trials, respectively, were performed to assist, through modeling and simulation, the selection of dosing regimens for phase III. Simulation of ANC predicted a decrease after a 5-day regimen of 60 mg/m(2) with partial recovery before the next cycle, whereas the nadir of 90 mg/m(2) on the same schedule was below 100/µl...
October 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28913897/studying-the-progression-of-amyloid-pathology-and-its-therapy-using-translational-longitudinal-model-of-accumulation-and-distribution-of-amyloid-beta
#16
Tatiana Karelina, Oleg Demin, Oleg Demin, Sridhar Duvvuri, Timothy Nicholas
Long-term effects of amyloid targeted therapy can be studied using a mechanistic translational model of amyloid beta (Aβ) distribution and aggregation calibrated on published data in mouse and human species. Alzheimer disease (AD) pathology is modeled utilizing age-dependent pathological evolution for rate constants and several variants of explicit functions for Aβ toxicity influencing cognitive outcomes (Adas-cog). Preventive Aβ targeted therapies were simulated to minimize the Aβ difference from healthy physiological levels...
October 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28782266/population-exposure-response-modeling-supported-selection-of-naloxegol-doses-in-phase-iii-studies-in-patients-with-opioid-induced-constipation
#17
Nidal Al-Huniti, Hongmei Xu, Diansong Zhou, Sergey Aksenov, Robert Fox, Khanh H Bui
Naloxegol is approved for the treatment of opioid-induced constipation (OIC) in adults with chronic noncancer pain. Population exposure-response models were developed using data from a phase II study comprising 185 adults with OIC. The weekly probability of response defined as having ≥3/week spontaneous bowel movements (SBMs) and ≥1 SBM/week increase over baseline was characterized by a longitudinal mixed-effects logistic regression dose-response model, and the probability of time to discontinuation was modeled with a Weibull distribution function...
October 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28699195/model-based-meta-analysis-on-the-efficacy-of-pharmacological-treatments-for-idiopathic-pulmonary-fibrosis
#18
Phyllis Chan, Leon Bax, Chunlin Chen, Nancy Zhang, Shu-Pang Huang, Holly Soares, Glenn Rosen, Malaz AbuTarif
Recently, the US Food and Drug Administration (FDA) approved the first two drugs (pirfenidone and nintedanib) indicated for the treatment of idiopathic pulmonary fibrosis (IPF). The purpose of this analysis was to leverage publicly available data to quantify comparative efficacy of compounds that are approved or in development. An analysis-ready database was developed, and the analysis dataset is composed of summary-level data from 43 arms in 20 trials, with treatment durations ranging from 8-104 weeks. A hierarchical multivariable regression model with nonparametric placebo estimation was used to fit the longitudinal profile of change from baseline of percent predicted forced vital capacity (%predicted FVC) data...
October 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28643440/model-description-language-mdl-a-standard-for-modeling-and-simulation
#19
Mike K Smith, Stuart L Moodie, Roberto Bizzotto, Eric Blaudez, Elisa Borella, Letizia Carrara, Phylinda Chan, Marylore Chenel, Emmanuelle Comets, Ronald Gieschke, Kajsa Harling, Lutz Harnisch, Niklas Hartung, Andrew C Hooker, Mats O Karlsson, Richard Kaye, Charlotte Kloft, Natallia Kokash, Marc Lavielle, Giulia Lestini, Paolo Magni, Andrea Mari, France Mentré, Chris Muselle, Rikard Nordgren, Henrik B Nyberg, Zinnia P Parra-Guillén, Lorenzo Pasotti, Niels Rode-Kristensen, Maria L Sardu, Gareth R Smith, Maciej J Swat, Nadia Terranova, Gunnar Yngman, Florent Yvon, Nick Holford
No abstract text is available yet for this article.
October 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28575551/pharmml-in-action-an-interoperable-language-for-modeling-and-simulation
#20
R Bizzotto, E Comets, G Smith, F Yvon, N R Kristensen, M J Swat
PharmML is an XML-based exchange format created with a focus on nonlinear mixed-effect (NLME) models used in pharmacometrics, but providing a very general framework that also allows describing mathematical and statistical models such as single-subject or nonlinear and multivariate regression models. This tutorial provides an overview of the structure of this language, brief suggestions on how to work with it, and use cases demonstrating its power and flexibility.
October 2017: CPT: Pharmacometrics & Systems Pharmacology
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