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CPT: Pharmacometrics & Systems Pharmacology

Diana Clausznitzer, Cesar Pichardo-Almarza, Ana Lucia Relo, Jeroen van Bergeijk, Elizabeth van der Kam, Loic Laplanche, Neil Benson, Marjoleen Nijsen
Alzheimer's Disease (AD) is a devastating neurodegenerative disorder with high unmet medical need. Drug development is hampered by limited understanding of the disease and its driving factors. Quantitative Systems Pharmacology (QSP) modeling provides a comprehensive quantitative framework to evaluate the relevance of biological mechanisms in the context of disease and to predict the efficacy of novel treatments. Here, we report a QSP model for AD with a particular focus on investigating the relevance of dysregulation of cholesterol and sphingolipids...
September 12, 2018: CPT: Pharmacometrics & Systems Pharmacology
Anisur Rahman, Abhinav Tiwari, Jatin Narula, Timothy Hickling
The human adaptive immune system is a very complex network of different types of cells, cytokines and signaling molecules. This complex network makes it difficult to understand the system level regulations. To properly explain the immune system, it is necessary to explicitly investigate the presence of different feedback and feedforward loops and their crosstalks. Considering these loops increases the complexity of the system. Mathematical modeling has been proved to be an important tool to explain such complex biological systems...
September 10, 2018: CPT: Pharmacometrics & Systems Pharmacology
Andrew M Stein, Lambertus A Peletier
When analyzing the pharmacokinetics (PK) of drugs, one is often faced with concentration C vs. time curves, which display a sharp transition at a critical concentration Ccrit . For C > Ccrit , the curve displays linear clearance and for C < Ccrit clearance increases in a nonlinear manner as C decreases. Often, it is important to choose a high enough dose such that PK remains linear in order to help ensure that continuous target engagement is achieved throughout the duration of therapy. In this article, we derive a simple expression for Ccrit for models involving linear and nonlinear (saturable) clearance, such as Michaelis-Menten and target-mediated drug disposition (TMDD) models...
September 8, 2018: CPT: Pharmacometrics & Systems Pharmacology
Takashi Yoshikado, Kota Toshimoto, Kazuya Maeda, Hiroyuki Kusuhara, Emi Kimoto, A David Rodrigues, Koji Chiba, Yuichi Sugiyama
The aim of the present study was to establish a physiologically-based pharmacokinetic model for coproporphyrin I (CP-I), a biomarker supporting the prediction of drug-drug interactions (DDIs) involving hepatic organic anion transporting polypeptide 1Bs (OATP1Bs), using clinical DDI data with an OATP1Bs inhibitor rifampicin (300 and 600 mg, orally). The in vivo inhibition constants of rifampicin used as initial input parameters for OATP1Bs (Ki,u, OATP 1Bs ) and multidrug resistance-associated protein 2-mediated biliary excretion were estimated as 0...
September 3, 2018: CPT: Pharmacometrics & Systems Pharmacology
Muhammad W Ashraf, Marko A Peltoniemi, Klaus T Olkkola, Pertti J Neuvonen, Teijo I Saari
Low-dose oral S-ketamine is increasingly used in chronic pain therapy, but extensive cytochrome P450 (CYP) mediated metabolism makes it prone to pharmacokinetic drug-drug interactions (DDIs). In our study, concentration-time data from five studies were used to develop a semimechanistic model that describes the ticlopidine-mediated inhibition of S-ketamine biotransformation. A mechanistic model was implemented to account for reversible and time-dependent hepatic CYP2B6 inactivation by ticlopidine, which causes elevated S-ketamine exposure in vivo...
August 9, 2018: CPT: Pharmacometrics & Systems Pharmacology
Nina Hanke, Sebastian Frechen, Daniel Moj, Hannah Britz, Thomas Eissing, Thomas Wendl, Thorsten Lehr
According to current US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidance documents, physiologically based pharmacokinetic (PBPK) modeling is a powerful tool to explore and quantitatively predict drug-drug interactions (DDIs) and may offer an alternative to dedicated clinical trials. This study provides whole-body PBPK models of rifampicin, itraconazole, clarithromycin, midazolam, alfentanil, and digoxin within the Open Systems Pharmacology (OSP) Suite. All models were built independently, coupled using reported interaction parameters, and mutually evaluated to verify their predictive performance by simulating published clinical DDI studies...
August 8, 2018: CPT: Pharmacometrics & Systems Pharmacology
Elin Boger, Oskar Wigström
The heterogeneous nature of the lungs and the range of processes affecting pulmonary drug disposition make prediction of inhaled drugs challenging. These predictions are critical, as the local exposure cannot be measured and current inhalation physiologically based pharmacokinetic (PBPK) models do not capture all necessary features. Utilizing partial differential equations, we present an inhalation PBPK model to describe the heterogeneity in both lung physiology and particle size. The model mechanistically describes important processes, such as deposition, mucociliary clearance, and dissolution...
August 7, 2018: CPT: Pharmacometrics & Systems Pharmacology
Xu Zhu, Xiaomeng Shen, Jun Qu, Robert M Straubinger, William J Jusko
Gemcitabine combined with birinapant, an inhibitor of apoptosis protein antagonist, acts synergistically to reduce pancreatic cancer cell proliferation. A large-scale proteomics dataset provided rich time-series data on proteome-level changes that reflect the underlying biological system and mechanisms of action of these drugs. A multiscale network model was developed to link the signaling pathways of cell cycle regulation, DNA damage response, DNA repair, apoptosis, nuclear factor-kappa β (NF-κβ), and mitogen-activated protein kinase (MAPK)-p38 to cell cycle progression, proliferation, and death...
August 7, 2018: CPT: Pharmacometrics & Systems Pharmacology
Benjamin Guiastrennec, David P Sonne, Martin Bergstrand, Tina Vilsbøll, Filip K Knop, Mats O Karlsson
Bile acids released postprandially can modify the rate and extent of lipophilic compounds' absorption. This study aimed to predict the enterohepatic circulation (EHC) of total bile acids (TBAs) in response to caloric intake from their spillover in plasma. A model for TBA EHC was combined with a previously developed gastric emptying (GE) model. Longitudinal gallbladder volumes and TBA plasma concentration data from 30 subjects studied after ingestion of four different test drinks were supplemented with literature data...
August 2, 2018: CPT: Pharmacometrics & Systems Pharmacology
Kris M Jamsen, Kashyap Patel, Keith Nieforth, Carl M J Kirkpatrick
A visual predictive check (VPC) is a common diagnostic procedure for population pharmacometric models. Typically, VPCs are generated by specifying intervals, or "bins", of an independent variable (e.g., time). However, bin specification is not always straightforward and the choice of bins may affect the appearance, and possibly conclusions, of VPCs. The objective of this work was to demonstrate how regression techniques can be used to derive VPCs and prediction-corrected VPCs (pcVPCs) for population pharmacometric models...
July 29, 2018: CPT: Pharmacometrics & Systems Pharmacology
Thomas Eissing
No abstract text is available yet for this article.
July 27, 2018: CPT: Pharmacometrics & Systems Pharmacology
James M Gallo
No abstract text is available yet for this article.
July 24, 2018: CPT: Pharmacometrics & Systems Pharmacology
Zufar Mulyukov, Sebastian Weber, Etienne Pigeolet, Andreas Clemens, Thorsten Lehr, Amy Racine
Intravitreal ranibizumab is a first-line therapy for neovascular age-related macular degeneration (nAMD), but there is a need to optimize patient outcomes while minimizing treatment burden. Here, we developed an indirect response, nonlinear, mixed effects model of disease progression and drug effect in anti-vascular endothelial growth factor (VEGF) treatment-naïve patients. A total of 1,524 treatment-naïve patients and 29,754 visual acuity observations from the ANCHOR, MARINA, PIER, and EXCITE clinical trials informed the model...
July 24, 2018: CPT: Pharmacometrics & Systems Pharmacology
Michiel J van Esdonk, Ian Lindeman, Pieter Okkerse, Marieke L de Kam, Geert J Groeneveld, Jasper Stevens
A battery of pain models can be used in clinical trials to investigate the efficacy and to establish the concentration-effect relationship of novel analgesics. This study quantified the pharmacokinetics (PK) of pregabalin after a single oral dose of 300 mg and the pharmacodynamics (PD) on the pain tolerance threshold (PTT) of the cold pressor, electrical stimulation, the pressure pain model, and on the pain detection threshold of a contact heat pain model. The PK were best described using a one-compartment model with lag time, linear absorption, and linear elimination...
July 24, 2018: CPT: Pharmacometrics & Systems Pharmacology
Konstantinos Biliouris, Puneet Gaitonde, Wei Yin, Daniel A Norris, Yanfeng Wang, Scott Henry, Robert Fey, Ivan Nestorov, Stephan Schmidt, Mark Rogge, Lawrence J Lesko, Mirjam N Trame
A pharmacokinetic (PK) model was developed for nusinersen, an antisense oligonucleotide (ASO) that is the first approved treatment for spinal muscular atrophy (SMA). The model was built with data from 92 nonhuman primates (NHPs) following intrathecal doses (0.3-7 mg) and characterized the PK in cerebrospinal fluid (CSF), plasma, total spinal cord, brain, and pons. The estimated volumes were 13.6, 937, 4.5, 53.8, and 2.11 mL, respectively. Global sensitivity analysis demonstrated that the CSF-to-plasma drug distribution rate (0...
July 24, 2018: CPT: Pharmacometrics & Systems Pharmacology
Chihiro Hasegawa, Stephen B Duffull
Integrating quantitative systems pharmacology (QSP) into pharmacokinetics/pharmacodynamics (PKPD) has resulted in models that are highly complex and often not amenable to further exploration via estimation or design. Because QSP models are usually depicted using nonlinear differential equations it is not straightforward to apply some model reduction techniques, such as proper lumping. In this study, we explore the combined use of linearization and proper lumping as a general method to simplification of a nonlinear QSP model...
July 24, 2018: CPT: Pharmacometrics & Systems Pharmacology
Weize Huang, Nina Isoherranen
Renal clearance is usually predicted via empirical approaches including quantitative structure activity relationship and allometric scaling. Recently, mechanistic prediction approaches using in silico kidney models have been proposed. However, empirical scaling factors are typically used to adjust for either passive diffusion or active secretion, to acceptably predict renal clearances. The goal of this study was to establish a renal clearance simulation tool that allows prediction of renal clearance (filtration and pH-dependent passive reabsorption) from in vitro permeability data...
July 24, 2018: CPT: Pharmacometrics & Systems Pharmacology
Kevin M Watt, Michael Cohen-Wolkowiez, Jeffrey S Barrett, Michael Sevestre, Ping Zhao, Kim L R Brouwer, Andrea N Edginton
Extracorporeal life support (e.g., dialysis, extracorporeal membrane oxygenation (ECMO)) can affect drug disposition, placing patients at risk for therapeutic failure. In this population, dose selection to achieve safe and effective drug exposure is difficult. We developed a novel and flexible approach that uses physiologically based pharmacokinetic (PBPK) modeling to translate results from ECMO ex vivo experiments into bedside dosing recommendations. To determine fluconazole dosing in children on ECMO, we developed a PBPK model, which was validated using fluconazole pharmacokinetic (PK) data in adults and critically ill infants...
July 22, 2018: CPT: Pharmacometrics & Systems Pharmacology
Heng-Yi Wu, Deshun Lu, Mustafa Hyder, Shijun Zhang, Sara K Quinney, Zeruesenay Desta, Lang Li
Drug metabolites (DMs) are critical in pharmacology research areas such as drug metabolism pathways and drug-drug interactions. However, there is no terminology dictionary containing comprehensive drug metabolite names, and there is no named entity recognition (NER) algorithm focusing on drug metabolite identification. In this paper, we developed a novel NER system, DrugMetab, to identify DMs from the PubMed abstracts. DrugMetab utilizes the features characterized from the Part-of-Speech, drug index and pre/suffix, and determines DMs within context...
July 22, 2018: CPT: Pharmacometrics & Systems Pharmacology
Nadia Terranova, Mike K Smith, Rikard Nordgren, Emmanuelle Comets, Marc Lavielle, Kajsa Harling, Andrew C Hooker, Celine Sarr, France Mentré, Florent Yvon, Maciej J Swat
No abstract text is available yet for this article.
July 22, 2018: CPT: Pharmacometrics & Systems Pharmacology
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