7 research outputs found
A Computational Systems Biology Software Platform for Multiscale Modeling and Simulation: Integrating Whole-Body Physiology, Disease Biology, and Molecular Reaction Networks
Today, in silico studies and trial simulations already complement experimental approaches in pharmaceutical R&D and have become indispensable tools for decision making and communication with regulatory agencies. While biology is multiscale by nature, project work, and software tools usually focus on isolated aspects of drug action, such as pharmacokinetics at the organism scale or pharmacodynamic interaction on the molecular level. We present a modeling and simulation software platform consisting of PK-SimĀ® and MoBiĀ® capable of building and simulating models that integrate across biological scales. A prototypical multiscale model for the progression of a pancreatic tumor and its response to pharmacotherapy is constructed and virtual patients are treated with a prodrug activated by hepatic metabolization. Tumor growth is driven by signal transduction leading to cell cycle transition and proliferation. Free tumor concentrations of the active metabolite inhibit Raf kinase in the signaling cascade and thereby cell cycle progression. In a virtual clinical study, the individual therapeutic outcome of the chemotherapeutic intervention is simulated for a large population with heterogeneous genomic background. Thereby, the platform allows efficient model building and integration of biological knowledge and prior data from all biological scales. Experimental in vitro model systems can be linked with observations in animal experiments and clinical trials. The interplay between patients, diseases, and drugs and topics with high clinical relevance such as the role of pharmacogenomics, drugādrug, or drugāmetabolite interactions can be addressed using this mechanistic, insight driven multiscale modeling approach
A generic framework for the physiologicallyābased pharmacokinetic platform qualification of PKāSim and its application to predicting cytochrome P450 3A4āmediated drugādrug interactions
Abstract The success of applications of physiologicallyābased pharmacokinetic (PBPK) modeling in drug development and drug labeling has triggered regulatory agencies to demand rigorous demonstration of the predictive capability of the specific PBPK platform for a particular intended application purpose. The effort needed to comply with such qualification requirements exceeds the costs for any individual PBPK application. Because changes or updates of a PBPK platform would require (reā)qualification, a reliable and efficient generic qualification framework is needed. We describe the development and implementation of an agile and sustainable technical framework for automatic PBPK platform (reā)qualification of PKāSimĀ® embedded in the open source and open science GitHub landscape of Open Systems Pharmacology. The qualification approach enables the efficient assessment of all aspects relevant to the qualification of a particular purpose and provides transparency and traceability for all stakeholders. As a showcase example for the power and versatility of the qualification framework, we present the qualification of PKāSimĀ® for the intended purpose of predicting cytochrome P450 3A4 (CYP3A4)āmediated drugādrug interactions (DDIs). Several perpetrator PBPK models featuring various degrees of CYP3A4 modulation and different types of mechanisms (competitive inhibition, mechanismābased inactivation, and induction) were coupled with a set of PBPK models of sensitive CYP3A4 victim drugs. Simulations were compared to a comprehensive data set of 135 observations from published clinical DDI studies. The platform's overall predictive performance showed reasonable accuracy and precision (geometric mean fold error of 1.4 for both area under the plasma concentrationātime curve ratios and peak plasma concentration ratios with/without perpetrator) and suggests that PKāSimĀ® can be applied to quantitatively assess CYP3A4āmediated DDI in clinically untested scenarios
A generic framework for the physiologicallyābased pharmacokinetic platform qualification of PKāSim and its application to predicting cytochrome P450 3A4āmediated drugādrug interactions
Abstract The success of applications of physiologicallyābased pharmacokinetic (PBPK) modeling in drug development and drug labeling has triggered regulatory agencies to demand rigorous demonstration of the predictive capability of the specific PBPK platform for a particular intended application purpose. The effort needed to comply with such qualification requirements exceeds the costs for any individual PBPK application. Because changes or updates of a PBPK platform would require (reā)qualification, a reliable and efficient generic qualification framework is needed. We describe the development and implementation of an agile and sustainable technical framework for automatic PBPK platform (reā)qualification of PKāSimĀ® embedded in the open source and open science GitHub landscape of Open Systems Pharmacology. The qualification approach enables the efficient assessment of all aspects relevant to the qualification of a particular purpose and provides transparency and traceability for all stakeholders. As a showcase example for the power and versatility of the qualification framework, we present the qualification of PKāSimĀ® for the intended purpose of predicting cytochrome P450 3A4 (CYP3A4)āmediated drugādrug interactions (DDIs). Several perpetrator PBPK models featuring various degrees of CYP3A4 modulation and different types of mechanisms (competitive inhibition, mechanismābased inactivation, and induction) were coupled with a set of PBPK models of sensitive CYP3A4 victim drugs. Simulations were compared to a comprehensive data set of 135 observations from published clinical DDI studies. The platform's overall predictive performance showed reasonable accuracy and precision (geometric mean fold error of 1.4 for both area under the plasma concentrationātime curve ratios and peak plasma concentration ratios with/without perpetrator) and suggests that PKāSimĀ® can be applied to quantitatively assess CYP3A4āmediated DDI in clinically untested scenarios
Open Systems Pharmacology Community-An Open Access, Open Source, Open Science Approach to Modeling and Simulation in Pharmaceutical Sciences
Systems pharmacology integrates structural biological and pharmacological knowledge and experimental data, enabling dissection of organism and drug properties and providing excellent predictivity. The development of systems pharmacology models is a significant task requiring massive amounts of background information beyond individual trial data. The qualification of models needs repetitive demonstration of successful predictions. Open Systems Pharmacology is a community that develops, qualifies, and shares professional open source software tools and models in a collaborative open-science way