Xenobiotic induction mechanisms affecting pharmacokinetics and pharmacodynamics among medically complex children, adolescents, and young adults.

Living organisms have evolved the capacity to cope with exposures to chemically diverse foreign entities, called xenobiotics. For humans, xenobiotics are frequently encountered from diet, cosmetics, industrial or agricultural products, environmental pollutants, and therapeutic drugs. Nearly all therapeutic drugs entering the body encounter the xenobiotic detoxication system (XDS) which acts to detect, chemically modify, and eliminate xenobiotics from the body. Therefore, the XDS governs drug safety and efficacy. However, the dynamic nature of the XDS is rarely considered when prescribing. Xenobiotic-triggered upregulation of the XDS is called induction. Evidence from my work indicates induction might be common in medically complex children, adolescents, and young adult (CAYA) patients who experience polypharmacy. A state of polypharmacy is prone to precipitate induction as well as cause broad disruptions in drug pharmacokinetics (PK) which can result in drug failure or toxicity. My central hypothesis is that xenobiotic- induced changes in the XDS are common, largely unrecognized, and contribute to suboptimal therapeutic outcomes for medically complex CAYA experiencing polypharmacy. In a clinical setting, assessing the phenomenon of induction is challenging and therefore rarely performed. Nonetheless, determining the frequency, magnitude, and triggering exposures for induction among medically complex CAYA could provide numerous opportunities to improve therapeutics use and benefit patient outcomes. My translational clinical pharmacology research program seeks to better understand factors that influence drug safety and efficacy in medically complex CAYA who experience polypharmacy. To accomplish this, I built a unique pharmacology platform (“PKPD platform”) to obtain much needed standard-of-care (‘real-world’) population- specific PK data. We found that blood concentrations, spanning commonly to rarely prescribed drugs across different pharmacologic classes were consistently lower than expected for achieving therapeutic target ranges. As polypharmacy is a near universal feature for medically complex CAYA, we began to suspect induction was an unrecognized but prevalent factor affecting drug therapy. In the timeframe of this proposal, we will use our PKPD platform to investigate the rate and magnitude of induction as well as causes and consequences of induction among medically complex CAYA. Additionally, we will evaluate a newly discovered mechanism of drug-induced changes to epigenetic regulator activity and the consequences for XDS gene expression. Project Number: 1R35GM160200-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: JONATHAN CONSTANCE | Institution: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH, SALT LAKE CITY, UT | Award Amount: $2,117,500 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 MCST-Q (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11202054