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CPT: Pharmacometrics & Systems Pharmacology

Sina Saffaran, Wenfei Wang, Anup Das, Walter Schmitt, Eva-Maria Becker-Pelster, Jonathan G Hardman, Gerrit Weimann, Declan G Bates
This study uses a highly fidelity computational simulator of pulmonary physiology to evaluate the impact of a soluble guanylate cyclase (sGC) modulator on gas exchange in patients with chronic obstructive pulmonary disease (COPD) and pulmonary hypertension (PH) as a complication. Three virtual patients with COPD were configured in the simulator based on clinical data. In agreement with previous clinical studies, modeling systemic application of an sGC modulator results in reduced partial pressure of oxygen (PaO2 ) and increased partial pressure of carbon dioxide (PaCO2 ) in arterial blood, if a drug-induced reduction of pulmonary vascular resistance (PVR) equal to that observed experimentally is assumed...
July 2, 2018: CPT: Pharmacometrics & Systems Pharmacology
Kenta Yoshida, Cen Guo, Rucha Sane
Quantitative prediction of the magnitude of transporter-mediated clinical drug-drug interactions (DDIs) solely from in vitro inhibition data remains challenging. The objective of the present work was to analyze kinetic profile of an endogenous biomarker for organic anion transporting polypeptides 1B (OATP1B), coproporphyrin I (CPI), and to predict clinical DDIs with a probe OATP1B substrate (pravastatin) based on "in vivo" inhibition constants (Ki ). CPI kinetics in the presence and absence of strong and weak OATP1B inhibitors (rifampin and GDC-0810) were described well with a one-compartment model, and in vivo Ki were estimated...
June 20, 2018: CPT: Pharmacometrics & Systems Pharmacology
Chanchala D Kaddi, Bradley Niesner, Rena Baek, Paul Jasper, John Pappas, John Tolsma, Jing Li, Zachary van Rijn, Mengdi Tao, Catherine Ortemann-Renon, Rachael Easton, Sharon Tan, Ana Cristina Puga, Edward H Schuchman, Jeffrey S Barrett, Karim Azer
Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with heterogeneous clinical manifestations, including hepatosplenomegaly and infiltrative pulmonary disease, and is associated with significant morbidity and mortality. Olipudase alfa (recombinant human acid sphingomyelinase) is an enzyme replacement therapy under development for the non-neurological manifestations of ASMD. We present a quantitative systems pharmacology (QSP) model supporting the clinical development of olipudase alfa...
June 19, 2018: CPT: Pharmacometrics & Systems Pharmacology
Yun Hao, Kayla Quinnies, Ronald Realubit, Charles Karan, Nicholas P Tatonetti
Understanding the downstream consequences of pharmacologically targeted proteins is essential to drug design. Current approaches investigate molecular effects under tissue-naïve assumptions. Many target proteins, however, have tissue-specific expression. A systematic study connecting drugs to target pathways in in vivo human tissues is needed. We introduced a data-driven method that integrates drug-target relationships with gene expression, protein-protein interaction, and pathway annotation data. We applied our method to four independent genomewide expression datasets and built 467,396 connections between 1,034 drugs and 954 pathways in 259 human tissues or cell lines...
June 19, 2018: CPT: Pharmacometrics & Systems Pharmacology
Chie Emoto, Trevor N Johnson, Sibylle Neuhoff, David Hahn, Alexander A Vinks, Tsuyoshi Fukuda
Morphine has large pharmacokinetic variability, which is further complicated by developmental changes in neonates and small infants. The impacts of organic cation transporter 1 (OCT1) genotype and changes in blood-flow on morphine clearance (CL) were previously demonstrated in children, whereas changes in UDP-glucuronosyltransferase 2B7 (UGT2B7) activity showed a small effect. This study, targeting neonates and small infants, was designed to assess the influence of developmental changes in OCT1 and UGT2B7 protein expression and modified blood-flow on morphine CL using physiologically based pharmacokinetic (PBPK) modeling...
June 19, 2018: CPT: Pharmacometrics & Systems Pharmacology
Toshimichi Nakamura, Kota Toshimoto, Wooin Lee, Chiyo K Imamura, Yusuke Tanigawara, Yuichi Sugiyama
The Tamoxifen Response by CYP2D6 Genotype-based Treatment-1 (TARGET-1) study (n = 180) was conducted from 2012-2017 in Japan to determine the efficacy of tamoxifen dosing guided by cytochrome P450 2D6 (CYP2D6) genotypes. To predict its outcomes prior to completion, we constructed the comprehensive physiologically based pharmacokinetic (PBPK) models of tamoxifen and its metabolites and performed virtual TARGET-1 studies. Our analyses indicated that the expected probability to achieve the end point (demonstrating the superior efficacy of the escalated tamoxifen dose over the standard dose in patients carrying CYP2D6 variants) was 0...
June 19, 2018: CPT: Pharmacometrics & Systems Pharmacology
Hitesh B Mistry
No abstract text is available yet for this article.
June 7, 2018: CPT: Pharmacometrics & Systems Pharmacology
Mirjam N Trame, Matthew Riggs, Kostas Biliouris, Dhananjay Marathe, Jerome Mettetal, Teun M Post, Matthew L Rizk, Sandra A G Visser, Cynthia J Musante
No abstract text is available yet for this article.
May 15, 2018: CPT: Pharmacometrics & Systems Pharmacology
Andrew M Stein, Michael Looby
No abstract text is available yet for this article.
May 15, 2018: CPT: Pharmacometrics & Systems Pharmacology
John K Diep, Thomas A Russo, Gauri G Rao
The emergence of highly resistant bacteria is a serious threat to global public health. The host immune response is vital for clearing bacteria from the infected host; however, the current drug development paradigm does not take host-pathogen interactions into consideration. Here, we used a systems-based approach to develop a quantitative, mechanism-based disease progression model to describe bacterial dynamics, host immune response, and lung injury in an immunocompetent rat pneumonia model. Previously, Long-Evans rats were infected with A...
May 15, 2018: CPT: Pharmacometrics & Systems Pharmacology
Daniel C Kirouac
No abstract text is available yet for this article.
May 15, 2018: CPT: Pharmacometrics & Systems Pharmacology
Janneke M Brussee, Huixin Yu, Elke H J Krekels, Berend de Roos, Margreke J E Brill, Johannes N van den Anker, Amin Rostami-Hodjegan, Saskia N de Wildt, Catherijne A J Knibbe
To predict first-pass and systemic cytochrome P450 (CYP) 3A-mediated metabolism of midazolam in preterm neonates, a physiological population pharmacokinetic model was developed describing intestinal and hepatic midazolam clearance in preterm infants. On the basis of midazolam and 1-OH-midazolam concentrations from 37 preterm neonates (gestational age 26-34 weeks) receiving midazolam orally and/or via a 30-minute intravenous infusion, intrinsic clearance in the gut wall and liver were found to be very low, with lower values in the gut wall (0...
May 10, 2018: CPT: Pharmacometrics & Systems Pharmacology
Moustafa M A Ibrahim, Siti M S Ghadzi, Maria C Kjellsson, Mats O Karlsson
In antidiabetic drug development, phase I studies usually involve short-term glucose provocations. Multiple designs are available for these provocations (e.g., meal tolerance tests (MTTs) and graded glucose infusions (GGIs)). With a highly nonlinear, complex system as the glucose homeostasis, the various provocations will contribute with different information offering a rich choice. Here, we investigate the most appropriate study design in phase I for several hypothetical mechanisms of action of a study drug...
May 6, 2018: CPT: Pharmacometrics & Systems Pharmacology
Paul B Watkins
The study by Mason et al. in this issue used mechanistic modeling and simulation to address how both the dose of acetaminophen consumed and the time since ingestion can be estimated from biomarkers measured in a single serum sample in mice. Translation into the clinic would potentially be an advance in the treatment of acetaminophen poisoning. Importantly, this approach could transform the evaluation of liver safety in clinical trials of new drug candidates.
April 26, 2018: CPT: Pharmacometrics & Systems Pharmacology
S Sanduja, P Jewell, E Aron, N Pharai
No abstract text is available yet for this article.
June 2018: CPT: Pharmacometrics & Systems Pharmacology
Pascal Schulthess, Rob C van Wijk, Elke H J Krekels, James W T Yates, Herman P Spaink, Piet H van der Graaf
To advance the systems approach in pharmacology, experimental models and computational methods need to be integrated from early drug discovery onward. Here, we propose outside-in model development, a model identification technique to understand and predict the dynamics of a system without requiring prior biological and/or pharmacological knowledge. The advanced data required could be obtained by whole vertebrate, high-throughput, low-resource dose-exposure-effect experimentation with the zebrafish larva. Combinations of these innovative techniques could improve early drug discovery...
May 2018: CPT: Pharmacometrics & Systems Pharmacology
Stefan Willmann, Liping Zhang, Matthias Frede, Dagmar Kubitza, Wolfgang Mueck, Stephan Schmidt, Alexander Solms, Xiaoyu Yan, Dirk Garmann
The population pharmacokinetics (PK) of rivaroxaban have been evaluated in several population-specific models. We developed an integrated population PK model using pooled data from 4,918 patients in 7 clinical trials across all approved indications. Effects of gender, age, and weight on apparent clearance (CL/F) and apparent volume of distribution (V/F), renal function, and comedication on CL/F, and relative bioavailability as a function of dose (F) were analyzed. Virtual subpopulations for exposure simulations were defined by age, creatinine clearance (CrCL) and body mass index (BMI)...
May 2018: CPT: Pharmacometrics & Systems Pharmacology
Cristiana Larizza, Elisa Borella, Lorenzo Pasotti, Palma Tartaglione, Mike Smith, Stuart Moodie, Paolo Magni
The Drug Disease Model Resources (DDMoRe) Interoperability Framework (IOF) enables pharmacometric model encoding and execution via Model Description Language (MDL) and R language, through the ddmore package. Through its components and converter plugins, the IOF can execute pharmacometric tasks using different target tools, starting from a single MDL-encoded model. In this article, we present the WinBUGS plugin and show how its integration in the IOF enables an easy implementation of complex Bayesian workflows...
May 2018: CPT: Pharmacometrics & Systems Pharmacology
Gustaf J Wellhagen, Mats O Karlsson, Maria C Kjellsson
Reusing published models saves time; time to be used for informing decisions in drug development. In antihyperglycemic drug development, several published HbA1c models are available but selecting the appropriate model for a particular purpose is challenging. This study aims at helping selection by investigating four HbA1c models, specifically the ability to identify drug effects (shape, site of action, and power) and simulation properties. All models could identify glucose effect nonlinearities, although for detecting the site of action, a mechanistic glucose model was needed...
May 2018: CPT: Pharmacometrics & Systems Pharmacology
Martin Boucher, Meg Bennetts
Meta-analyses typically assess comparative treatment response for an end point at specific timepoints across studies. However, during drug development, it is often of interest to understand the response time-course of competitor compounds for a variety of purposes. Examples of such application include informing study design and characterizing the onset, maintenance, and offset of action. This tutorial acts as a "points for consideration" document, reviews relevant literature, and fits a longitudinal model to an example dataset...
May 2018: CPT: Pharmacometrics & Systems Pharmacology
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