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CPT: Pharmacometrics & Systems Pharmacology

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https://www.readbyqxmd.com/read/28782266/population-exposure-response-modeling-supported-selection-of-naloxegol-doses-in-phase-3-studies-in-patients-with-opioid-induced-constipation
#1
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
https://www.readbyqxmd.com/read/28782239/integration-of-genome-scale-metabolic-networks-and-gene-regulation-of-metabolic-enzymes-with-physiologically-based-pharmacokinetics
#2
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
https://www.readbyqxmd.com/read/28748626/combining-bottom-up-and-top-down-approaches-to-assess-the-impact-of-food-and-gastric-ph-on-pictilisib-gdc-0941-pharmacokinetics
#3
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
https://www.readbyqxmd.com/read/28699195/model-based-meta-analysis-on-the-efficacy-of-pharmacological-treatments-for-idiopathic-pulmonary-fibrosis
#4
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
https://www.readbyqxmd.com/read/28681552/logic-modeling-in-quantitative-systems-pharmacology
#5
Pauline Traynard, Luis Tobalina, Federica Eduati, Laurence Calzone, Julio Saez-Rodriguez
No abstract text is available yet for this article.
July 6, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28657202/assessing-pharmacodynamic-interactions-in-mice-using-the-multistate-tuberculosis-pharmacometric-and-general-pharmacodynamic-interaction-models
#6
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
https://www.readbyqxmd.com/read/28653357/pharmacokinetics-of-monoclonal-antibodies
#7
Josiah T Ryman, Bernd Meibohm
No abstract text is available yet for this article.
June 27, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28643440/model-description-language-mdl-a-standard-for-modelling-and-simulation
#8
EDITORIAL
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
https://www.readbyqxmd.com/read/28643388/a-longitudinal-item-response-theory-model-to-characterize-cognition-over-time-in-elderly-subjects
#9
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 most information on 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 of 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 1750 elderly subjects for up to 13...
June 23, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28643374/population-pharmacokinetic-and-pharmacodynamic-modeling-of-ly2510924-in-patients-with-advanced-cancer
#10
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
https://www.readbyqxmd.com/read/28643370/developing-a-natural-history-progression-model-for-duchenne-muscular-dystrophy-using-the-six-minute-walk-test
#11
Lora Hamuro, Phyllis Chan, Giridhar Tirucherai, Malaz AbuTarif
The six 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 meter/year (9.4-30, 95% confidence interval (CI)) up until 10 years old (6.78-13.1, 95% CI), and then decline at a rate of 85 meter/year (72-98, 95% CI)...
June 23, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28623849/population-pharmacokinetics-pharmacodynamics-of-3-4-diaminopyridine-free-base-in-patients-with-lambert-eaton-myasthenia
#12
Nilay Thakkar, Jeffrey T Guptill, Kathy Aleš, David Jacobus, Laura Jacobus, Charles Peloquin, Michael Cohen-Wolkowiez, Daniel Gonzalez
Lambert-Eaton Myasthenia (LEM) is a rare autoimmune disorder associated with debilitating muscle weakness. There are limited treatment options and 3,4-diaminopyridine free base (3,4-DAP) is an investigational orphan drug used to treat LEM-related weakness. We performed a population PK/PD analysis using 3,4-DAP and metabolite concentrations collected from a phase 2 study in LEM patients. The Triple Timed Up & Go (3TUG) assessment, which measures lower extremity weakness, was the primary outcome measure. A total of 1270 PK samples (49 patients) and 1091 3TUG data points (32 randomized patients) were included in the PK/PD analysis...
June 17, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28614899/determination-of-plasma-concentration-reference-ranges-for-risperidone-and-paliperidone
#13
Julia Korell, Bruce Green, Bart Remmerie, An Vermeulen
Schizophrenia is a common disease managed by a range of interventions with the primary treatment being antipsychotic medications (APS). Inadequate response, lack of adherence, and/or adverse events often prevent optimal therapeutic effects or therapeutic efficiency. Monitoring APS plasma concentrations can be used together with a full clinical evaluation to help improve patient care or offer better treatment options for the patient. To enable interpretation of individual risperidone and paliperidone plasma concentrations, we developed 'reference ranges', which consider the expected variability in plasma concentrations between subjects across the population, rather than representing a 'therapeutic range' that relates to efficacy and/or safety outcomes...
June 14, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28599102/obituary-for-matt-hutmacher
#14
EDITORIAL
Sunny Chapel, Kenneth G Kowalski
No abstract text is available yet for this article.
June 9, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28585415/methodologies-for-quantitative-systems-pharmacology-models-qsp-design-and-estimation
#15
EDITORIAL
B Ribba, H P Grimm, B Agoram, M R Davies, K Gadkar, S Niederer, N van Riel, J Timmis, P H van der Graaf
No abstract text is available yet for this article.
June 6, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28575552/supervised-machine-learning-reveals-that-old-and-obese-people-achieve-low-dapsone-concentrations
#16
Ronald G Hall, Jotam G Pasipanodya, Mark A Swancutt, Claudia Meek, Richard Leff, Tawanda 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 kilograms, 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...
June 2, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28575551/pharmml-in-action-an-interoperable-language-for-modelling-and-simulation
#17
Roberto Bizzotto, Emmanuelle Comets, Gareth Smith, Florent Yvon, Niels Rode Kristensen, Maciej Swat
No abstract text is available yet for this article.
June 2, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28575547/implications-for-drug-characterization-in-glucose-tolerance-tests-without-insulin-simulation-study-of-power-and-predictions-using-model-based-analysis
#18
Siti M Sheikh Ghadzi, Mats O Karlsson, Maria C Kjellsson
In anti-hyperglycemic drug development, drug effects are usually characterized using glucose provocations. Analyzing provocation data using pharmacometrics has been shown powerful, enabling small studies. In pre-clinical drug development, high power is attractive due to the experiment sizes, however insulin is not always available, which potentially impacts power and predictive performance. This simulation study was performed to investigate the implications of performing model-based drug characterization without insulin...
June 2, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28575540/optimizing-antipsychotic-patient-management-using-population-pharmacokinetic-models-and-point-of-care-testing
#19
EDITORIAL
Bruce Green, Julia Korell, Bart Remmerie, Adam Savitz, An Vermeulen
No abstract text is available yet for this article.
June 2, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28571121/mechanistic-oral-absorption-modeling-and-simulation-for-formulation-development-and-bioequivalence-evaluation-report-of-an-fda-public-workshop
#20
EDITORIAL
Xinyuan Zhang, John Duan, Filippos Kesisoglou, Jasmina Novakovic, Gordon Amidon, Masoud Jamei, Viera Lukacova, Thomas Eissing, Eleftheria Tsakalozou, Liang Zhao, Robert Lionberger
No abstract text is available yet for this article.
June 1, 2017: CPT: Pharmacometrics & Systems Pharmacology
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