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CPT: Pharmacometrics & Systems Pharmacology

Tatiana Karelina, O Demin, Oleg Demin, Sridhar Duvvuri, Timothy Nicholas
Long term effects of amyloid targeted therapy can be studied using a mechanistic translational model of Aβ distribution and aggregation calibrated on published data in mouse and human species. AD pathology is modelled 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. Therapeutic targeted simulations provided similar predictions for mouse and human...
September 15, 2017: CPT: Pharmacometrics & Systems Pharmacology
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
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, Johan 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, two cerebrospinal fluid sites, and total brain tissue...
September 11, 2017: CPT: Pharmacometrics & Systems Pharmacology
Bing Wang, Chi-Yuan Wu, Denise Jin, Paolo Vicini, Lorin Roskos
No abstract text is available yet for this article.
August 24, 2017: CPT: Pharmacometrics & Systems Pharmacology
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 non-cancer pain. Population exposure-response models were developed using data from a Phase 2 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...
August 7, 2017: CPT: Pharmacometrics & Systems Pharmacology
Elaina M Maldonado, Vytautas Leoncikas, Ciarán P Fisher, J Bernadette Moore, Nick J Plant, Andrzej M Kierzek
The scope of Physiologically Based Pharmacokinetic (PBPK) modelling can be expanded by assimilation of the mechanistic models of intracellular processes from Systems Biology field. Genome Scale Metabolic Networks (GSMNs) represent a whole set of metabolic enzymes expressed in human tissues. Dynamic models of the gene regulation of key drug metabolism enzymes are available. Here, we introduce GSMNs and review ongoing work on integration of PBPK, GSMNs and metabolic gene regulation. We demonstrate example models...
August 7, 2017: CPT: Pharmacometrics & Systems Pharmacology
Tong Lu, Grazyna Fraczkiewicz, Laurent Salphati, Nageshwar Budha, Gena Dalziel, Gillian S Smelick, Kari M Morrissey, John D Davis, Jin Y Jin, Joseph A Ware
Pictilisib, a weakly basic compound, is an orally administered, potent, and selective pan-inhibitor of phosphatidylinositol 3-kinases for oncology indications. To investigate the significance of high-fat food and gastric pH on pictilisib pharmacokinetics (PK) and enable label recommendations, a dedicated clinical study was conducted in healthy volunteers, whereby both top-down [Population PK, (PopPK)] and bottom-up [physiologically-based PK, (PBPK)] approaches were applied to enhance confidence of recommendation and facilitate the clinical development through scenario simulations...
July 27, 2017: CPT: Pharmacometrics & Systems Pharmacology
Phyllis Chan, Leon Bax, Chunlin Chen, Nancy Zhang, Shu-Pang Huang, Holly Soares, Glenn Rosen, Malaz AbuTarif
Recently the 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 to 104 weeks. A hierarchical multivariable regression model with non-parametric placebo estimation was used to fit the longitudinal profile of change from baseline of percent predicted forced vital capacity (%predicted FVC) data...
July 11, 2017: CPT: Pharmacometrics & Systems Pharmacology
Chunli Chen, Sebastian G Wicha, Gerjo J de Knegt, Fatima Ortega, Laura Alameda, Veronica Sousa, Jurriaan E M de Steenwinkel, Ulrika S H Simonsson
The aim of this study was to investigate pharmacodynamic interactions in mice infected with Mycobacterium tuberculosis using population pharmacokinetics, the Multistate Tuberculosis Pharmacometric (MTP) model, and the General Pharmacodynamic Interaction (GPDI) model. Rifampicin, isoniazid, ethambutol or pyrazinamide were administered in monotherapy for 4 weeks. Rifampicin and isoniazid showed effects in monotherapy, whereas the animals became moribund after 7 days with ethambutol or pyrazinamide alone. No pharmacodynamic interactions were observed against fast-multiplying bacteria...
June 28, 2017: CPT: Pharmacometrics & Systems Pharmacology
Josiah T Ryman, Bernd Meibohm
No abstract text is available yet for this article.
June 27, 2017: CPT: Pharmacometrics & Systems Pharmacology
M K Smith, S L Moodie, R Bizzotto, E Blaudez, E Borella, L Carrara, P Chan, M Chenel, E Comets, R Gieschke, K Harling, L Harnisch, N Hartung, A C Hooker, M O Karlsson, R Kaye, C Kloft, N Kokash, M Lavielle, G Lestini, P Magni, A Mari, F Mentré, C Muselle, R Nordgren, H Bjugård Nyberg, Z P Parra-Guillén, L Pasotti, N Rode-Kristensen, M L Sardu, G R Smith, M J Swat, N Terranova, G Yngman, F Yvon, N Holford
No abstract text is available yet for this article.
June 23, 2017: CPT: Pharmacometrics & Systems Pharmacology
Marc Vandemeulebroecke, Björn Bornkamp, Tillmann Krahnke, Johanna Mielke, Andreas Monsch, Peter Quarg
For drug development in neurodegenerative diseases such as Alzheimer's disease, it is important to understand which cognitive domains carry the most information on the earliest signs of cognitive decline, and which subject characteristics are associated with a faster decline. A longitudinal Item Response Theory (IRT) model was developed for the Basel Study on the Elderly, in which the Consortium to Establish a Registry for Alzheimer's Disease - Neuropsychological Assessment Battery (with additions) and the California Verbal Learning Test were measured on 1,750 elderly subjects for up to 13...
June 23, 2017: CPT: Pharmacometrics & Systems Pharmacology
S Bihorel, E Raddad, J Fiedler-Kelly, J R Stille, J Hing, E Ludwig
The objectives of this study were to characterize the pharmacokinetics (PK) of LY2510924, a potent peptide antagonist of the CXCR4 receptor, after subcutaneous administration in patients with advanced cancer forms and quantify LY2510924 stimulatory effects on the mobilization of cells bearing the cluster of differentiation 34 (CD34) as an indirect reflection of the chemokine C-X-C motif ligand 12/CXCR4 axis inhibition. LY2510924 PK were best characterized by a 2-compartment model with first-order absorption and dose-dependent clearance predicting steady state after three daily doses and little accumulation (accumulation ratio <1...
June 23, 2017: CPT: Pharmacometrics & Systems Pharmacology
Lora Hamuro, Phyllis Chan, Giridhar Tirucherai, Malaz AbuTarif
The 6-minute walk test (6MWT) is used as a clinical endpoint to evaluate drug efficacy in Duchenne Muscular Dystrophy (DMD) trials. A model was developed using digitized 6MWT data that estimated two slopes and two intercepts to characterize 6MWT improvement during development and 6MWT decline. Mean baseline 6MWT was 362 (±87) meters. The model predicted an improvement at a rate of 20 meters/year (95% confidence interval (CI) = 9.4-30) up until 10 years old (95% CI = 6.78-13.1), and then a decline at a rate of 85 meters/year (95% CI = 72-98)...
June 23, 2017: CPT: Pharmacometrics & Systems Pharmacology
Pauline Traynard, Luis Tobalina, Federica Eduati, Laurence Calzone, Julio Saez-Rodriguez
Here we present logic modeling as an approach to understand deregulation of signal transduction in disease and to characterize a drug's mode of action. We discuss how to build a logic model from the literature and experimental data and how to analyze the resulting model to obtain insights of relevance for systems pharmacology. Our workflow uses the free tools OmniPath (network reconstruction from the literature), CellNOpt (model fit to experimental data), MaBoSS (model analysis), and Cytoscape (visualization)...
August 2017: CPT: Pharmacometrics & Systems Pharmacology
S Chapel, K G Kowalski
No abstract text is available yet for this article.
August 2017: CPT: Pharmacometrics & Systems Pharmacology
B Ribba, H P Grimm, B Agoram, M R Davies, K Gadkar, S Niederer, N van Riel, J Timmis, P H van der Graaf
With the increased interest in the application of quantitative systems pharmacology (QSP) models within medicine research and development, there is an increasing need to formalize model development and verification aspects. In February 2016, a workshop was held at Roche Pharma Research and Early Development to focus discussions on two critical methodological aspects of QSP model development: optimal structural granularity and parameter estimation. We here report in a perspective article a summary of presentations and discussions...
August 2017: CPT: Pharmacometrics & Systems Pharmacology
R G Hall, J G Pasipanodya, M A Swancutt, C Meek, R Leff, T Gumbo
The human species is becoming increasingly obese. Dapsone, which is extensively used across the globe for dermatological disorders, arachnid bites, and for treatment of several bacterial, fungal, and parasitic diseases, could be affected by obesity. We performed a clinical experiment, using optimal design, in volunteers weighing 44-150 kg, to identify the effect of obesity on dapsone pharmacokinetic parameters based on maximum-likelihood solution via the expectation-maximization algorithm. Artificial intelligence-based multivariate adaptive regression splines were used for covariate selection, and identified weight and/or age as predictors of absorption, systemic clearance, and volume of distribution...
August 2017: CPT: Pharmacometrics & Systems Pharmacology
X Zhang, J Duan, F Kesisoglou, J Novakovic, G L Amidon, M Jamei, V Lukacova, T Eissing, E Tsakalozou, L Zhao, R Lionberger
On May 19, 2016, the US Food and Drug Administration (FDA) hosted a public workshop, entitled "Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation." The topic of mechanistic oral absorption modeling, which is one of the major applications of physiologically based pharmacokinetic (PBPK) modeling and simulation, focuses on predicting oral absorption by mechanistically integrating gastrointestinal transit, dissolution, and permeation processes, incorporating systems, active pharmaceutical ingredient (API), and the drug product information, into a systemic mathematical whole-body framework...
August 2017: CPT: Pharmacometrics & Systems Pharmacology
S Pilari, T Gaub, M Block, L Görlitz
We extended a generic whole-body physiologically based pharmacokinetic (PBPK) model for rats and humans for organs of the reproductive and endocrine systems (i.e., the testes and the thyroid gland). An extensive literature search was performed, first, to determine the most generic organ model structures for testes and thyroid across species, and, second, to identify the corresponding anatomic and physiological parameters in rats and humans. The testes and thyroid organ models were implemented in the PBPK modeling software PK-Sim and MoBi...
August 2017: CPT: Pharmacometrics & Systems Pharmacology
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