Pharmaceutical Technology - March 2021

Pharmaceutical Technology - Regulatory Sourcebook - March 2021

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24 Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2021 P h a r mTe c h . c o m Quality Collaboration P redictive sciences—built on improved computational capabilities and a deeper understanding of human physiology—are allowing researchers to perform human studies prior to, and sometimes in place of, human clinical trials in order to predict drug outcomes. Rep- resentatives of the Translational & ADME Sciences Leadership Group (TALG) in the IQ Consortium review the basic principles of physiologically-based pharmacokinetic (PBPK) modeling and its impact in streamlining the drug development process. Over the past two decades, significant advances have been made in the areas of modeling the disposition, efficacy, and safety of drugs to streamline clinical development and increase the probability of success (1). One approach is the use of PBPK modeling (2). PBPK models are mathematical platforms that integrate system parameters (species physiology) and drug characteristics to simulate the PK of a drug (3–5). These models have progressed from simple equations to sophisticated soft- ware tools representing different body compartments, under- lying physiology and biology, multiple drug components, and interindividual variability (3). Basic PBPK models define system-dependent parameters by volume, blood flow rate, and species-specific tissue composition (3). The simplest PBPK models assume perfusion rate limited dis- tribution within the "well-stirred" model (6), with clearance attributed to the liver and kidney. In advanced PBPK models, gut absorption is sub-compartmentalized into different regions of the gastrointestinal tract. Patients taking drugs with food can impact drug absorption and thus PK properties of the drugs, which can also be simulated (7). PBPK modeling may require a variable degree of parameterization using in-vitro and in-vivo data depending on the question the model is intended to ad- dress. Essential drug-specific parameters required for model execution will vary with the drug absorption, distribution, me- tabolism, and excretion (ADME) properties and the formula- tion in which it is administered. Typically, sensitivity analysis is employed to assess the model uncertainty and identify and in- vestigate parameters with the greatest impact on the simulation output (3), and clinical data are used to refine the mechanistic PBPK models further. In practice, a combination of approaches Heidi J. Einolf, Stephen D. Hall, Tracy Williams, Aarti Patel, Christopher Gibson, Nancy G.B. Agrawal, and Jens Sydor; all authors are members of the IQ Consortium. PAULISTA - STOCK.ADOBE.COM Enabling the Virtual Human Through Physiologically-based Pharmacokinetic Modeling Advances in computational sciences and better understanding of human physiology are enabling researchers to better predict drug outcomes. Representatives of the IQ Consortium's Translational & ADME Sciences Leadership Group report on recent studies and advances.

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