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CPT: Pharmacometrics & Systems Pharmacology

Edward C Stites, Andrey S Shaw
KRAS has proven difficult to target pharmacologically. Two strategies have recently been described for covalently targeting the most common KRAS mutant in lung cancer, KRAS G12C. Previously, we developed a computational model of the processes that regulate Ras activation. Here, we use this model to investigate KRAS G12C covalent inhibitors. We updated the model to include Ras protein turnover, and validation demonstrates that our model performs well in areas of G12C targeting where conventional wisdom struggles...
February 27, 2018: CPT: Pharmacometrics & Systems Pharmacology
Venkatesh Pilla Reddy, Michael Walker, Pradeep Sharma, Peter Ballard, Karthick Vishwanathan
Osimertinib is a potent, highly selective, irreversible inhibitor of Epidermal Growth Factor Receptor and T790M resistance mutation receptor. In vitro metabolism data suggested osimertinib is a substrate of CYP3A4/5, a weak inducer of CYP3A and an inhibitor of BCRP. A combination of in vitro data, clinical pharmacokinetic data and drug-drug interaction (DDI) data of osimertinib in oncology patients were used to develop the physiologically based pharmacokinetic (PBPK) model and verify the DDI data of osimertinib...
February 22, 2018: CPT: Pharmacometrics & Systems Pharmacology
Yingying Zhang, Zide Zhao, Yanan Yu, Jun Liu, Pengqian Wang, Bing Li, Xiaoxu Zhang, Yinying Chen, Zhong Wang
Identifying the variation of core modules and hubs seems to be critical for characterizing variable pharmacological mechanisms based on topological alteration of disease networks. We firstly identified a total of 8 core modules by using an approach of multiple modular characteristic fusing (MMCF) from different targeted networks in ischemic mice. Interestingly, the value of module disturbance intensity (MDI) increased in drug combination group. Secondly, we redefined a weak allosteric module and a strong allosteric module...
February 21, 2018: CPT: Pharmacometrics & Systems Pharmacology
Lang Li
No abstract text is available yet for this article.
February 19, 2018: CPT: Pharmacometrics & Systems Pharmacology
Chie Emoto, Trevor N Johnson, Brooks T McPhail, Alexander A Vinks, Tsuyoshi Fukuda
Simultaneous changes in several physiological factors may contribute to the large pharmacokinetic (PK) variability of vancomycin. This study was designed to systematically characterize the effects of multiple physiological factors to the altered PK of vancomycin observed in special populations. A vancomycin physiologically based pharmacokinetic (PBPK) model was developed as a PK simulation platform to quantitatively assess the effects of changes in physiologies to the PK profiles. The developed model predicted the concentration-time profiles in healthy adults and diseased patients...
February 15, 2018: CPT: Pharmacometrics & Systems Pharmacology
Youwei Bi, Paul J Perry, Michael Ellerby, Daryl J Murry
A randomized, double-blind clinical trial was conducted to investigate long-term abuse effects of testosterone cypionate. Thirty-one healthy males were randomized into a dose group of 100, 250 or 500mg/wk and received 14 weekly injections of TC. A PK-PD model was developed to characterize testosterone concentrations and link exposure to change in luteinizing hormone and spermatogenesis following long-term TC administration. A linear one-compartment model best described the concentration-time profile of total testosterone...
February 13, 2018: CPT: Pharmacometrics & Systems Pharmacology
Elisa A M Calvier, Elke H J Krekels, Huixin Yu, Pyry A J Välitalo, Trevor N Johnson, Amin Rostami-Hodjegan, Dick Tibboel, Piet H van der Graaf, Meindert Danhof, Catherijne A J Knibbe
For scaling drug plasma clearance (CLp) from adults to children, extrapolations of population pharmacokinetic (PopPK) covariate models between drugs sharing an elimination pathway have enabled accelerated development of pediatric models and dosing recommendations. This study aims at identifying conditions for which this approach consistently leads to accurate pathway specific CLp scaling from adults to children for drugs undergoing hepatic metabolism. A physiologically based pharmacokinetic (PBPK) simulation workflow utilizing mechanistic equations defining hepatic metabolism was developed...
February 5, 2018: CPT: Pharmacometrics & Systems Pharmacology
N Terranova, P Girard, K Ioannou, U Klinkhardt, A Munafo
Mathematical models of tumor dynamics generally omit information on individual target lesions (iTLs), and consider the most important variable to be the sum of tumor sizes (TS). However, differences in lesion dynamics might be predictive of tumor progression. To exploit this information, we have developed a novel and flexible approach for the non-parametric analysis of iTLs, which integrates knowledge from signal processing and machine learning. We called this new methodology ClassIfication Clustering of Individual Lesions (CICIL)...
February 1, 2018: CPT: Pharmacometrics & Systems Pharmacology
Anne Kümmel, Peter Bonate, Jasper Dingemanse, Andreas Krause
No abstract text is available yet for this article.
February 1, 2018: CPT: Pharmacometrics & Systems Pharmacology
Jialin Mao, Utkarsh Doshi, Matthew Wright, Cornelis E C A Hop, Albert P Li, Yuan Chen
Plateable human hepatocytes with human plasma were utilized to generate the uptake transporter kinetic data for pravastatin, an organic anion transporting polypeptide (OATP) transporter substrate. The active hepatic uptake of pravastatin was determined with a Jmax value of 134.4 pmol/min/million cells and apparent Km of 76.77 µM in plateable human hepatocytes with human plasma. The physiologically based pharmacokinetic (PBPK) model with incorporation of these in vitro kinetic data successfully simulated the intravenous pharmacokinetic profile of pravastatin without applying scaling factor (the mean predicted AUC is within 1...
February 1, 2018: CPT: Pharmacometrics & Systems Pharmacology
Doris H Fuertinger, Alice Topping, Franz Kappel, Stephan Thijssen, Peter Kotanko
In silico approaches have been proposed as a novel strategy to increase the repertoire of clinical trial designs. Realistic simulations of clinical trials can provide valuable information regarding safety and limitations of treatment protocols and have been shown to assist in the cost-effective planning of clinical studies. In this report, we present a blueprint for the stepwise integration of internal, external, and ecological validity considerations in virtual clinical trials (VCTs). We exemplify this approach in the context of a model-based in silico clinical trial aimed at anemia treatment in patients undergoing hemodialysis (HD)...
January 25, 2018: CPT: Pharmacometrics & Systems Pharmacology
Ryuta Asaumi, Kota Toshimoto, Yoshifusa Tobe, Kenta Hashizume, Ken-Ichi Nunoya, Haruo Imawaka, Wooin Lee, Yuichi Sugiyama
This study aimed to construct a physiologically based pharmacokinetic (PBPK) model of rifampicin that can accurately and quantitatively predict complex drug-drug interactions (DDIs) involving its saturable hepatic uptake and auto-induction. Using in silico and in vitro parameters, and reported clinical pharmacokinetic data, rifampicin PBPK model was built and relevant parameters for saturable hepatic uptake and UDP-glucuronosyltransferase auto-induction were optimized by fitting. The parameters for cytochrome P450 (CYP) 3A and CYP2C9 induction by rifampicin were similarly optimized using clinical DDI data with midazolam and tolbutamide as probe substrates, respectively...
January 25, 2018: CPT: Pharmacometrics & Systems Pharmacology
Marjoleen J M A Nijsen, Fan Wu, Loveleena Bansal, Erica Bradshaw-Pierce, Jason R Chan, Bianca M Liederer, Jerome T Mettetal, Patricia Schroeder, Edgar Schuck, Alice Tsai, Christine Xu, Anjaneya Chimalakonda, Kha Le, Mark Penney, Brian Topp, Akihiro Yamada, Mary E Spilker
No abstract text is available yet for this article.
January 19, 2018: CPT: Pharmacometrics & Systems Pharmacology
Dimitris E Messinis, Ioannis N Melas, Junguk Hur, Navya Varshney, Leonidas G Alexopoulos, Jane P F Bai
Drug-induced cardiomyopathy contributes to drug attrition. We compared two pipelines of predictive modeling: (1) applying elastic net (EN) to differentially expressed genes (DEGs) of drugs; (2) applying integer linear programming (ILP) to construct each drug's signaling pathway starting from its targets to downstream proteins, to transcription factors, and to its DEGs in human cardiomyocytes, and then subjecting the genes/proteins in the drugs' signaling networks to EN regression. We classified 31 drugs with availability of DEGs into 13 toxic and 18 nontoxic drugs based on a clinical cardiomyopathy incidence cutoff of 0...
January 17, 2018: CPT: Pharmacometrics & Systems Pharmacology
Sebastian Ueckert
Composite assessments aim to combine different aspects of a disease in a single score and are utilized in a variety of therapeutic areas. The data arising from these evaluations are inherently discrete with distinct statistical properties. This tutorial presents the framework of the item response theory (IRT) for the analysis of this data type in a pharmacometric context. The article considers both conceptual (terms and assumptions) and practical questions (modeling software, data requirements, and model building)...
January 13, 2018: CPT: Pharmacometrics & Systems Pharmacology
Ying Zhang, Michael A Tortorici, Dipti Pawaskar, Ingo Pragst, Thomas Machnig, Matthew Hutmacher, Bruce Zuraw, Marco Cicardi, Timothy Craig, Hilary Longhurst, Jagdev Sidhu
Subcutaneous C1-inhibitor (HAEGARDA, CSL Behring), is a US Food and Drug Administration (FDA)-approved, highly concentrated formulation of a plasma-derived C1-esterase inhibitor (C1-INH), which, in the phase III Clinical Studies for Optimal Management in Preventing Angioedema with Low-Volume Subcutaneous C1-inhibitor Replacement Therapy (COMPACT) trial, reduced the incidence of hereditary angioedema (HAE) attacks when given prophylactically. Data from the COMPACT trial were used to develop a repeated time-to-event model to characterize the timing and frequency of HAE attacks as a function of C1-INH activity, and then develop an exposure-response model to assess the relationship between C1-INH functional activity levels (C1-INH(f)) and the risk of an attack...
January 9, 2018: CPT: Pharmacometrics & Systems Pharmacology
Ramon Hendrickx, Eva Lamm Bergström, David L I Janzén, Markus Fridén, Ulf Eriksson, Ken Grime, Douglas Ferguson
Translational pharmacokinetic (PK) models are needed to describe and predict drug concentration-time profiles in lung tissue at the site of action to enable animal-to-man translation and prediction of efficacy in humans for inhaled medicines. Current pulmonary PK models are generally descriptive rather than predictive, drug/compound specific, and fail to show successful cross-species translation. The objective of this work was to develop a robust compartmental modeling approach that captures key features of lung and systemic PK after pulmonary administration of a set of 12 soluble drugs containing single basic, dibasic, or cationic functional groups...
December 27, 2017: CPT: Pharmacometrics & Systems Pharmacology
Alice Ban Ke, Rick Greupink, Khaled Abduljalil
The unmet medical need of providing evidence-based pharmacotherapy for pregnant women is recognized by the regulatory bodies. Physiologically based pharmacokinetic (PBPK) modeling offers an attractive platform to quantify anticipated changes in the pharmacokinetics (PKs) of drugs during pregnancy. Recent publications applying a pregnancy PBPK module to the prediction of maternal and fetal exposure of drugs are summarized. Future opportunities to use PBPK models to predict breast milk exposure and assess human fetotoxicity risks are presented...
February 2018: CPT: Pharmacometrics & Systems Pharmacology
Sara K Quinney, Rakesh Gullapelli, David M Haas
Pregnancy involves rapid physiological adaptation and complex interplay between mother and fetus. New analytic technologies provide large amounts of genomic, proteomic, and metabolomics data. The integration of these data through bioinformatics, statistical, and systems pharmacology techniques can improve our understanding of the mechanisms of normal maternal physiologic changes and fetal development. New insights into the mechanisms of pregnancy-related disorders, such as preterm birth (PTB), may lead to the development of new therapeutic interventions and novel biomarkers...
February 2018: CPT: Pharmacometrics & Systems Pharmacology
Pengyue Zhang, Heng-Yi Wu, Chien-Wei Chiang, Lei Wang, Samar Binkheder, Xueying Wang, Donglin Zeng, Sara K Quinney, Lang Li
Drug interaction is a leading cause of adverse drug events and a major obstacle for current clinical practice. Pharmacovigilance data mining, pharmacokinetic modeling, and text mining are computation and informatic tools on integrating drug interaction knowledge and generating drug interaction hypothesis. We provide a comprehensive overview of these translational biomedical informatics methodologies with related databases. We hope this review illustrates the complementary nature of these informatic approaches and facilitates the translational drug interaction research...
February 2018: CPT: Pharmacometrics & Systems Pharmacology
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