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CPT: Pharmacometrics & Systems Pharmacology

Sergey Ermakov, Brian J Schmidt, Cynthia J Musante, Craig J Thalhauser
Quantitative Systems Pharmacology is a rapidly emerging discipline with application across a spectrum of challenges facing the pharmaceutical industry, including mechanistically informed prioritization of target pathways and combinations in discovery, target population and dose expansion decisions early in clinical development, and analyses for regulatory authorities late in clinical development. Quantitative Systems Pharmacology's development has influences from physiologic modeling, systems biology, physiologically-based pharmacokinetic modeling, and pharmacometrics...
November 12, 2018: CPT: Pharmacometrics & Systems Pharmacology
Scott Marshall, Rajanikanth Madabushi, Efthymios Manolis, Kevin Krudys, Alexander Staab, Kevin Dykstra, Sandra A G Visser
Good practices around model-informed drug discovery development (MID3) aim to improve the implementation, standardization, and acceptance of these approaches within drug development and regulatory review. A survey targeted to clinical pharmacology and pharmacometric colleagues across industry, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) was conducted to understand current and future role of MID3. The documented standards were generally affirmed as a "good match" to current industry practice and regulatory expectations; with some identified gaps that are discussed...
November 8, 2018: CPT: Pharmacometrics & Systems Pharmacology
Matt McDaniel, Jenn Carter, Jon Keller, Steven White, Austin Baird
BioGears is an open-source, lumped parameter, full-body human physiology engine. Its purpose is to provide realistic and comprehensive simulations for medical training, research, and education. BioGears incorporates a physiologically-based pharmacokinetic/pharmacodynamic (PK/PD) model that is designed to be applicable to a diversity of drug classes and patients and is extensible to future drugs. In addition, BioGears also supports drug interactions with various patient insults and interventions allowing for a realistic research framework and accurate dose-patient responses...
November 8, 2018: CPT: Pharmacometrics & Systems Pharmacology
Li Li, Hongcan Han, Jun Wang, Chunmin Wei, Yuzhu Wang, Min Li, Yu Zhou, Jinbo Yang
Since 2016, the Center for Drug Evaluation, National Medical Product Agency has routinely received and reviewed modeling and simulation (M&S) analyses submitted at different stages of drug development. A series of related guidelines were released. The perspective identifies opportunities and challenges in applying M&S in drug regulation in China. Model informed drug development (MiDD) and regulation have played important roles in drug development worldwide. This article is protected by copyright. All rights reserved...
November 8, 2018: CPT: Pharmacometrics & Systems Pharmacology
Lokesh Jain, Nitin Mehrotra, Larissa Wenning, Vikram Sinha
With years of experience in modeling and simulation (M&S), and model informed drug development (MIDD) as one of the goals in PDUFA VI authorization, it is now the right time to apply MIDD for high impact decisions. Over the last two decades, current applications of MIDD in drug discovery, dose selection, benefit-risk assessment, and labeling have been useful. The value proposition of M&S is acknowledged in the PDUFA VI authorization, which provides an excellent opportunity for industry and regulators to collaborate in further advancing the applications of MIDD, potentially changing drug development paradigms...
October 28, 2018: CPT: Pharmacometrics & Systems Pharmacology
Suruchi Bakshi, Vijayalakshmi Chelliah, Chao Chen, Piet H van der Graaf
Parkinsons disease (PD) is a progressive neurodegenerative disease with substantial and growing socio-economic burden. In this multifactorial disease, aging, environmental, and genetic factors contribute to neurodegeneration and dopamine (DA) deficiency in the brain. Treatments aimed at DA restoration provide symptomatic relief, however, no disease modifying treatments are available, and PD remains incurable to date. Mathematical modeling can help understand such complex multifactorial neurological diseases...
October 25, 2018: CPT: Pharmacometrics & Systems Pharmacology
Peter Schotland, Rebecca Racz, David Jackson, Robert Levin, David G Strauss, Keith Burkhart
Clinical trials can fail to detect rare adverse events (AEs). We assessed the ability of pharmacological target adverse-event (TAE) profiles to predict AEs on US Food and Drug Administration (FDA) drug labels at least 4 years after approval. TAE profiles were generated by aggregating AEs from the FDA adverse event reporting system (FAERS) reports and the FDA drug labels for drugs that hit a common target. A genetic algorithm (GA) was used to choose the adverse event (AE) case count (N), disproportionality score in FAERS (proportional reporting ratio (PRR)), and percent of comparator drug labels with an AE to maximize F-measure...
October 24, 2018: CPT: Pharmacometrics & Systems Pharmacology
Karin Jorga, Bruno Reigner, Clarisse Chavanne, Giuseppe Alvaro, Nicolas Frey
Intravenous ganciclovir and oral valganciclovir are effective in the prevention and treatment of pediatric cytomegalovirus (CMV) infection but various dosing regimens are used in medical practice. Population pharmacokinetic model-based simulations were used to propose a new ganciclovir pediatric dosing algorithm for regulatory review and to evaluate the approved valganciclovir pediatric dosing algorithm against published dosing recommendations derived from quantitative approaches. Oral valganciclovir (mg=7×BSA×CrCLS daily) and intravenous ganciclovir (mg=3×BSA×CrCLS daily) are effective in reaching ganciclovir target exposure for the prevention of CMV (AUC0-24 40-60 μg...
October 24, 2018: CPT: Pharmacometrics & Systems Pharmacology
Yu Kyoung Cho, Donald J Irby, Junan Li, Douglas W Sborov, Diane R Mould, Mohamed Badawi, Anees Dauki, Misty Lamprecht, Ashley E Rosko, Soledad Fernandez, Erinn M Hade, Craig C Hofmeister, Ming Poi, Mitch A Phelps
High-dose melphalan (HDM) is part of the conditioning regimen in patients with multiple myeloma (MM) receiving autologous stem cell transplantation (ASCT). However, individual sensitivity to melphalan varies, and many patients experience severe toxicities. Prolonged severe neutropenia is one of the most severe toxicities and contributes to potentially life-threatening infections and failure of ASCT. Granulocyte-colony stimulating factor (G-CSF) is given to stimulate neutrophil proliferation after melphalan administration...
October 20, 2018: CPT: Pharmacometrics & Systems Pharmacology
Christian Lüpfert, Martin Dyroff, Oliver von Richter, Dieter Gallemann, Samer El Bawab, Hugues Dolgos, Don Jung, Stefan Hecht, Andreas Johne
Evofosfamide is a cytotoxic small-molecule prodrug preferentially activated under hypoxic conditions. The cytotoxicity of evofosfamide impacted the generation of in vitro drug-drug interaction (DDI) data, especially in vitro induction results. Therefore, a novel physiologically based pharmacokinetic (PBPK) approach was used, which involved available in vitro and clinical data of evofosfamide and combined it with induction data from the prototypical cytochrome P450 (CYP)3A inducer rifampicin. The area under the concentration-time curve (AUC) ratios of midazolam were above 0...
October 12, 2018: CPT: Pharmacometrics & Systems Pharmacology
Surulivelrajan Mallayasamy, Ayyappa Chaturvedula, Terrence Blaschke, Michael J Fossler
The objective of our study was to evaluate the effect of adherence patterns on the sample size and power of a clinical trial. Simulations from a population pharmacokinetic/pharmacodynamic (PK/PD) model linked to an adherence model were used. Four types of drug characteristics, such as long (~35 hours) and short (~12 hours) half-life in combination with earlier or delayed time to reach steady-state PD end points were studied. Adherence patterns were simulated using Markov chains. Our results clearly demonstrate the significant impact of varying levels and patterns of nonadherence on the sample size and power of a study...
October 5, 2018: CPT: Pharmacometrics & Systems Pharmacology
Pavel Balazki, Stephan Schaller, Thomas Eissing, Thorsten Lehr
The early stage of diabetes mellitus is characterized by increased glomerular filtration rate (GFR), known as hyperfiltration, which is believed to be one of the main causes leading to renal injury in diabetes. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to be able to reverse hyperfiltration in some patients. We developed a mechanistic computational model of the kidney that explains the interplay of hyperglycemia and hyperfiltration and integrates the pharmacokinetics/pharmacodynamics (PK/PD) of the SGLT2i dapagliflozin...
September 30, 2018: CPT: Pharmacometrics & Systems Pharmacology
Lawrence C Ku, Christoph P Hornik, Ryan J Beechinor, James M Chamberlain, Jeffrey T Guptill, Barrie Harper, Edmund V Capparelli, Karen Martz, Ravinder Anand, Michael Cohen-Wolkowiez, Daniel Gonzalez
Diazepam is labeled for status epilepticus (SE) in children, but there are limited data characterizing its disposition in pediatric patients. We developed a population pharmacokinetic (PK) model of i.v. diazepam in children with SE. We evaluated relationships between PK parameters and both safety and efficacy, and simulated exposures using dosing regimens from the product label and clinical practice. The model was developed using prospective data from a pediatric clinical trial comparing diazepam to lorazepam for treatment of SE...
September 28, 2018: CPT: Pharmacometrics & Systems Pharmacology
Jeffry Adiwidjaja, Alan V Boddy, Andrew J McLachlan
The phenotyping approach to predict drug metabolism activity is often hampered by a lack of correlation between the probe and the drug of interest. In this article, we present a strategy to refine the phenotyping approach based on a physiologically based pharmacokinetic simulation (implemented in Simcyp Simulator version 17) using previously published models. The apparent clearance (CL/F) of erlotinib was better predicted by the sum of caffeine and i.v. midazolam CL/F (r2  = 0.60) compared to that of either probe drug alone...
September 27, 2018: CPT: Pharmacometrics & Systems Pharmacology
Lawrence J Lesko, Valvanera Vozmediano, Joshua D Brown, Almut Winterstein, Ping Zhao, Jörg Lippert, Joachim Höchel, Ayyappa Chaturvedula, Annesha White, Stephan Schmidt
Hormonal contraceptive agents (HCAs) are widely used throughout the world, and women taking HCAs are likely to take other medications. However, little is known about clinical effect of most drug-drug interactions (DDIs) associated with HCAs. A team of interdisciplinary outcomes and pharmacometric researchers from academia and industry jointly engage in a research project to (1) quantitatively elucidate DDI impacts on unintended pregnancies and breakthrough bleeding, and (2) establish a DDI-prediction framework to inform optimal use of HCAs...
September 27, 2018: CPT: Pharmacometrics & Systems Pharmacology
Brenda Cirincione, Kenneth Kowalski, Jace Nielsen, Amit Roy, Neelima Thanneer, Wonkyung Byon, Rebecca Boyd, Xiaoli Wang, Tarek Leil, Frank LaCreta, Takayo Ueno, Masayo Oishi, Charles Frost
This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I-III studies. Apixaban exposure was characterized by a two-compartment PPK model with first-order absorption and elimination. Predictive covariates on apparent clearance included age, sex, Asian race, renal function, and concomitant strong/moderate cytochrome P450 (CYP)3A4/P-glycoprotein (P-gp) inhibitors...
September 27, 2018: CPT: Pharmacometrics & Systems Pharmacology
Ron J Keizer, Rob Ter Heine, Adam Frymoyer, Lawrence J Lesko, Ranvir Mangat, Srijib Goswami
The development of model-informed precision dosing (MIPD) tools, especially in the form of native or web-based applications to be used at the bedside, has garnered marked attention in recent years. Their potential clinical benefit can be large, but it should be ensured that such tools make optimal use of available clinical data and have adequate predictive ability. Unique scientific challenges specific to MIPD remain, which may require adaptation of commonly used diagnostics in pharmacometrics.
September 25, 2018: CPT: Pharmacometrics & Systems Pharmacology
John David Clements, Juan Jose Perez Ruixo, John P Gibbs, Sameer Doshi, Carlos Perez Ruixo, Murad Melhem
Optimal dose selection in clinical trials is problematic when efficacious and toxic concentrations are close. A novel quantitative approach follows for optimizing dose titration in clinical trials. A system of pharmacokinetics (PK), pharmacodynamics, efficacy, and toxicity was simulated for scenarios characterized by varying degrees of different types of variability. Receiver operating characteristic (ROC) and clinical trial simulation (CTS) were used to optimize drug titration by maximizing efficacy/safety...
September 23, 2018: 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
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 (PBPK) model for coproporphyrin I (CP-I), a biomarker supporting the prediction of drug-drug interactions (DDIs) involving hepatic organic anion transporting polypeptide 1B (OATP1B), using clinical DDI data with an OATP1B inhibitor rifampicin (300 and 600 mg, orally). The in vivo inhibition constants of rifampicin used as initial input parameters for OATP1Bs (Ki,u,OATP1Bs ) and multidrug resistance-associated protein two-mediated biliary excretion were estimated as 0...
September 3, 2018: CPT: Pharmacometrics & Systems Pharmacology
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