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A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions.

ABSTRACT: All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies.

SUBMITTER: Cherkaoui-Rbati MH

PROVIDER: S-EPMC5598964 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:More than 50 million adults in America suffer from chronic pain. Opioids are commonly prescribed for their effectiveness in relieving many types of pain. However, excessive prescribing of opioids can lead to abuse, addiction, and death. Non-steroidal anti-inflammatory drugs (NSAIDs), another major class of analgesic, also have many problematic side effects including headache, dizziness, vomiting, diarrhea, nausea, constipation, reduced appetite, and drowsiness. There is an urgent need for the understanding of molecular mechanisms that underlie drug abuse and addiction to aid in the design of new preventive or therapeutic agents for pain management. To facilitate pain related small-molecule signaling pathway studies and the prediction of potential therapeutic target(s) for the treatment of pain, we have constructed a comprehensive platform of a pain domain-specific chemogenomics knowledgebase (Pain-CKB) with integrated data mining computing tools. Our new computing platform describes the chemical molecules, genes, proteins, and signaling pathways involved in pain regulation. Pain-CKB is implemented with a friendly user interface for the prediction of the relevant protein targets and analysis and visualization of the outputs, including HTDocking, TargetHunter, BBB predictor, and Spider Plot. Combining these with other novel tools, we performed three case studies to systematically demonstrate how further studies can be conducted based on the data generated from Pain-CKB and its algorithms and tools. First, systems pharmacology target mapping was carried out for four FDA approved analgesics in order to identify the known target and predict off-target interactions. Subsequently, the target mapping outcomes were applied to build physiologically based pharmacokinetic (PBPK) models for acetaminophen and fentanyl to explore the drug-drug interaction (DDI) between this pair of drugs. Finally, pharmaco-analytics was conducted to explore the detailed interaction pattern of acetaminophen reactive metabolite and its hepatotoxicity target, thioredoxin reductase.

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A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions.

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