About

Dr. Breanna Howell, OTD, OTR/L, is a Clinical Assistant Professor at the Sensory Development Lab within the Department of Occupational Therapy at the University of Florida. She earned her Bachelor of Science in Health Science from Stetson University and completed both her Master of Arts in Occupational Therapy and Doctor of Occupational Therapy degrees at the University of Southern California. Dr. Howell has extensive clinical experience working with children who have a variety of conditions including autism spectrum disorder, genetic conditions, cerebral palsy, Down syndrome, anxiety, sensory processing differences, spina bifida, learning disabilities, and feeding difficulties. Her expertise encompasses sensory processing, feeding, constraint-induced movement therapy (CIMT), social skills and self-regulation, augmentative and alternative communication (AAC), the Therasuit method, and aquatic therapy. In her role at the Sensory Development Lab, Dr. Howell provides research interventions and supports the development of intervention studies, contributing to the lab's mission to advance understanding and treatment of sensory processing and related challenges in pediatric populations. Outside of her professional work, Dr. Howell enjoys spending time with her puppy, watching sunsets at the beach, and relaxing in her hammock.

Research topics

• Medicine
• Internal medicine
• Pharmacology

Selected publications

• Modeling and Simulation of Acetaminophen Pharmacokinetics and Hepatic Biomarkers After Overdoses of Extended‐Release and Immediate‐Release Formulations in Healthy Adults Using the Quantitative Systems Toxicology Software Platform <scp>DILIsym</scp>

  CPT Pharmacometrics & Systems Pharmacology · 2025-02-03 · 4 citations

  articleOpen access

  Acetaminophen (APAP) has been formulated as immediate-, modified-, and extended-release tablets (APAP-IR, -MR, and -ER, respectively). However, there was concern that APAP-MR previously available in Europe could form a bezoar after a large overdose, leading to delayed absorption and atypical pharmacokinetics (PK) compared to APAP-IR, and that current treatment guidelines developed for APAP overdose to prevent severe hepatotoxicity are inappropriate for APAP-MR. In contrast, APAP-ER caplets available in the United States are designed with an IR layer and an erodible ER layer. Using modeling and simulation, predicted PK and hepatotoxicity biomarkers following various acute overdose and repeated supratherapeutic ingestion (RSTI) scenarios with APAP-IR and APAP-ER were compared to investigate the differences between these two formulations. The existing APAP-IR representation within DILIsym v8A, a quantitative systems toxicology model of drug-induced liver injury, was updated, and an APAP-ER model was developed, using newly acquired in vitro (e.g., tiny-TIMsg) and clinical data. The model and simulated populations (SimPops) representing healthy adults were extensively validated, before simulating PK and three clinically useful hepatic biomarkers after various overdose scenarios. On average, APAP exposure after acute overdose and RSTI in healthy adults was predicted to be slightly lower for APAP-ER compared to APAP-IR, partially due to lower APAP absorption for APAP-ER, while not markedly impacting the expected time course of APAP plasma concentrations. Similar hepatic biomarker profiles were predicted for both APAP formulations. Based on these results, the APAP overdose consensus treatment guidelines updated in 2023 are not further impacted by this report.

  PublisherOA PDFDOI

• Quantitative Systems Toxicology Modeling of Acetaminophen Pharmacokinetics and Hepatic Biomarkers After Overdoses of Extended‐Release and Immediate‐Release Formulations in Adults With Chronic Alcohol Use or Low Glutathione

  CPT Pharmacometrics & Systems Pharmacology · 2025-05-14

  articleOpen access

  Acetaminophen (APAP), an over-the-counter analgesic and antipyretic, can cause hepatotoxicity when ingested in large overdoses. APAP has multiple formulations including immediate-release (IR) and extended-release (ER) preparations. A recently published consensus statement on the management of APAP poisoning indicated that management of APAP-ER overdose is the same as that for APAP-IR overdose. Consistent with this consensus, it was previously reported that quantitative systems toxicology (QST) modeling using DILIsym predicted similar pharmacokinetic (PK) and hepatic biomarker profiles for the APAP-ER and APAP-IR formulations after overdose in healthy adults. Hepatic injury from APAP is caused by the reactive metabolite, N-acetyl-ρ-benzoquinone imine (NAPQI), which is formed predominantly by CYP2E1-mediated metabolism and eliminated by hepatic glutathione. As such, conditions that can increase NAPQI production (e.g., CYP2E1 induction by alcohol) or decrease hepatic glutathione stores (e.g., underling liver disease) may impact PK and susceptibility to hepatotoxicity after overdose of APAP-IR and APAP-ER. In the current study, APAP-IR and APAP-ER models in chronic alcohol users and individuals with low hepatic glutathione were developed and verified within DILIsym. Simulations using verified models predicted similar PK and hepatic biomarker profiles for the APAP-ER and APAP-IR formulations in moderate and excessive chronic alcohol users and adults with low hepatic glutathione levels after single acute overdoses up to ~100 g and repeat supratherapeutic ingestions (up to 7.8 g/day for 10 days). These results further support that approaches to manage APAP-IR overdoses can be applied to manage APAP-ER overdoses in adults with chronic alcohol consumption or lower hepatic glutathione levels.

  PublisherOA PDFDOI

• Quantitative Systems Toxicology Modeling of Otenaproxesul Liver Enzyme Elevations Leads to Prediction of Liver Safety for Acute Otenaproxesul Dosing

  2024-01-01

  articleOpen accessSenior author
  PublisherDOI

• Prediction of the liver safety profile of a first-in-class myeloperoxidase inhibitor using quantitative systems toxicology modeling

  Xenobiotica · 2024-06-14 · 3 citations

  articleSenior author

  experiments measured the likelihood that verdiperstat would inhibit mitochondrial function, inhibit bile acid transporters, and generate reactive oxygen species (ROS); these results were used as inputs into DILIsym, with two alternate sets of parameters used in order to fully explore the sensitivity of model predictions. Verdiperstat dosing protocols up to 600 mg BID were simulated for up to 48 weeks using a simulated population (SimPops) in DILIsym.Verdiperstat was predicted to be safe, with only very rare, mild liver enzyme increases as a potential possibility in highly sensitive individuals. Subsequent Phase 3 clinical trials found that ALT elevations in the verdiperstat treatment group were generally similar to those in the placebo group. This validates the DILIsym simulation results and demonstrates the power of QST modelling to predict the liver safety profile of novel therapeutics.

  PublisherDOI

• Simulated CD8+ T Cell-Mediated Liver Injury During Ipilimumab Administration in a Simulated Population (SimPops®) Demonstrates Profiles Consistent with Observed Clinical Data

  2024-01-01

  articleOpen access
  PublisherDOI

• Investigating bile acid-mediated cholestatic drug-induced liver injury using a mechanistic model of multidrug resistance protein 3 (MDR3) inhibition

  UNC Libraries · 2023-02-03

  articleOpen access

  Inhibition of the canalicular phospholipid floppase multidrug resistance protein 3 (MDR3) has been implicated in cholestatic drug-induced liver injury (DILI), which is clinically characterized by disrupted bile flow and damage to the biliary epithelium. Reduction in phospholipid excretion, as a consequence of MDR3 inhibition, decreases the formation of mixed micelles consisting of bile acids and phospholipids in the bile duct, resulting in a surplus of free bile acids that can damage the bile duct epithelial cells, i.e., cholangiocytes. Cholangiocytes may compensate for biliary increases in bile acid monomers via the cholehepatic shunt pathway or bicarbonate secretion, thereby influencing viability or progression to toxicity. To address the unmet need to predict drug-induced bile duct injury in humans, DILIsym, a quantitative systems toxicology model of DILI, was extended by representing key features of the bile duct, cholangiocyte functionality, bile acid and phospholipid disposition, and cholestatic hepatotoxicity. A virtual, healthy representative subject and population (n = 285) were calibrated and validated utilizing a variety of clinical data. Sensitivity analyses were performed for 1) the cholehepatic shunt pathway, 2) biliary bicarbonate concentrations and 3) modes of MDR3 inhibition. Simulations showed that an increase in shunting may decrease the biliary bile acid burden, but raise the hepatocellular concentrations of bile acids. Elevating the biliary concentration of bicarbonate may decrease bile acid shunting, but increase bile flow rate. In contrast to competitive inhibition, simulations demonstrated that non-competitive and mixed inhibition of MDR3 had a profound impact on phospholipid efflux, elevations in the biliary bile acid-to-phospholipid ratio, cholangiocyte toxicity, and adaptation pathways. The model with its extended bile acid homeostasis representation was furthermore able to predict DILI liability for compounds with previously studied interactions with bile acid transport. The cholestatic liver injury submodel in DILIsym accounts for several processes pertinent to bile duct viability and toxicity and hence, is useful for predictions of MDR3 inhibition-mediated cholestatic DILI in humans.

  PublisherDOI

• The Combination of a Human Biomimetic Liver Microphysiology System with BIOLOGXsym, a Quantitative Systems Toxicology (QST) Modeling Platform for Macromolecules, Provides Mechanistic Understanding of Tocilizumab- and GGF2-Induced Liver Injury

  International Journal of Molecular Sciences · 2023-06-02 · 13 citations

  articleOpen access

  Biologics address a range of unmet clinical needs, but the occurrence of biologics-induced liver injury remains a major challenge. Development of cimaglermin alfa (GGF2) was terminated due to transient elevations in serum aminotransferases and total bilirubin. Tocilizumab has been reported to induce transient aminotransferase elevations, requiring frequent monitoring. To evaluate the clinical risk of biologics-induced liver injury, a novel quantitative systems toxicology modeling platform, BIOLOGXsym™, representing relevant liver biochemistry and the mechanistic effects of biologics on liver pathophysiology, was developed in conjunction with clinically relevant data from a human biomimetic liver microphysiology system. Phenotypic and mechanistic toxicity data and metabolomics analysis from the Liver Acinus Microphysiology System showed that tocilizumab and GGF2 increased high mobility group box 1, indicating hepatic injury and stress. Tocilizumab exposure was associated with increased oxidative stress and extracellular/tissue remodeling, and GGF2 decreased bile acid secretion. BIOLOGXsym simulations, leveraging the in vivo exposure predicted by physiologically-based pharmacokinetic modeling and mechanistic toxicity data from the Liver Acinus Microphysiology System, reproduced the clinically observed liver signals of tocilizumab and GGF2, demonstrating that mechanistic toxicity data from microphysiology systems can be successfully integrated into a quantitative systems toxicology model to identify liabilities of biologics-induced liver injury and provide mechanistic insights into observed liver safety signals.

  PublisherOA PDFDOI

• Investigating bile acid-mediated cholestatic drug-induced liver injury using a mechanistic model of multidrug resistance protein 3 (MDR3) inhibition

  Frontiers in Pharmacology · 2023-01-17 · 7 citations

  articleOpen access

  Inhibition of the canalicular phospholipid floppase multidrug resistance protein 3 (MDR3) has been implicated in cholestatic drug-induced liver injury (DILI), which is clinically characterized by disrupted bile flow and damage to the biliary epithelium. Reduction in phospholipid excretion, as a consequence of MDR3 inhibition, decreases the formation of mixed micelles consisting of bile acids and phospholipids in the bile duct, resulting in a surplus of free bile acids that can damage the bile duct epithelial cells, i.e., cholangiocytes. Cholangiocytes may compensate for biliary increases in bile acid monomers via the cholehepatic shunt pathway or bicarbonate secretion, thereby influencing viability or progression to toxicity. To address the unmet need to predict drug-induced bile duct injury in humans, DILIsym, a quantitative systems toxicology model of DILI, was extended by representing key features of the bile duct, cholangiocyte functionality, bile acid and phospholipid disposition, and cholestatic hepatotoxicity. A virtual, healthy representative subject and population ( n = 285) were calibrated and validated utilizing a variety of clinical data. Sensitivity analyses were performed for 1) the cholehepatic shunt pathway, 2) biliary bicarbonate concentrations and 3) modes of MDR3 inhibition. Simulations showed that an increase in shunting may decrease the biliary bile acid burden, but raise the hepatocellular concentrations of bile acids. Elevating the biliary concentration of bicarbonate may decrease bile acid shunting, but increase bile flow rate. In contrast to competitive inhibition, simulations demonstrated that non-competitive and mixed inhibition of MDR3 had a profound impact on phospholipid efflux, elevations in the biliary bile acid-to-phospholipid ratio, cholangiocyte toxicity, and adaptation pathways. The model with its extended bile acid homeostasis representation was furthermore able to predict DILI liability for compounds with previously studied interactions with bile acid transport. The cholestatic liver injury submodel in DILIsym accounts for several processes pertinent to bile duct viability and toxicity and hence, is useful for predictions of MDR3 inhibition-mediated cholestatic DILI in humans.

  PublisherOA PDFDOI

• Mechanistic investigation of liver injury induced by BMS-932481, an experimental ɣ-secretase modulator

  Toxicological Sciences · 2023-06-01 · 7 citations

  article

  BMS-932481 was designed to modulate ɣ-secretase activity to produce shorter and less amyloidogenic peptides, potentially averting liabilities associated with complete enzymatic inhibition. Although it demonstrated the intended pharmacology in the clinic, BMS-932481 unexpectedly caused drug-induced liver injury (DILI) in a multiple ascending dose study characterized by dose- and exposure-dependence, delayed onset manifestation, and a high incidence of hepatocellular damage. Retrospective studies investigating the disposition and probable mechanisms of toxicity of BMS-932481 are presented here. These included a mass balance study in bile-duct-cannulated rats and a metabolite profiling study in human hepatocytes, which together demonstrated oxidative metabolism followed by biliary elimination as the primary means of disposition. Additionally, minimal protein covalent binding in hepatocytes and lack of bioactivation products excluded reactive metabolite formation as a probable toxicological mechanism. However, BMS-932481 and 3 major oxidative metabolites were found to inhibit the bile salt export pump (BSEP) and multidrug resistance protein 4 (MRP4) in vitro. Considering human plasma concentrations, the IC50 values against these efflux transporters were clinically meaningful, particularly in the high dose cohort. Active uptake into human hepatocytes in vitro suggested the potential for hepatic levels of BMS-932481 to be elevated further above plasma concentrations, enhancing DILI risk. Conversely, measures of mitochondrial functional decline in hepatocytes treated with BMS-932481 were minimal or modest, suggesting limited contributions to DILI. Collectively, these findings suggested that repeat administration of BMS-932481 likely resulted in high hepatic concentrations of BMS-932481 and its metabolites, which disrupted bile acid transport via BSEP and MRP4, elevating serum biomarkers of liver injury.

  PublisherDOI

• Assessing Liver Effects of Cannabidiol and Valproate Alone and in Combination Using Quantitative Systems Toxicology

  Clinical Pharmacology & Therapeutics · 2023-07-17 · 17 citations

  article

  In clinical trials of cannabidiol (CBD) for the treatment of seizures in patients with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex, elevations in serum alanine aminotransferase (ALT) > 3× the upper limit of normal were observed in some patents, but the incidence was much greater in patients who were receiving treatment with valproate (VPA) before starting CBD. To explore potential mechanisms underlying this interaction, we used DILIsym, a quantitative systems toxicology model, to predict ALT elevations in a simulated human population treated with CBD alone, VPA alone, and when CBD dosing was starting during treatment with VPA. We gathered in vitro data assessing the potential for CBD, the two major CBD metabolites, and VPA to cause hepatotoxicity via inhibition of bile acid transporters, mitochondrial dysfunction, and production of reactive oxygen species (ROS). Physiologically-based pharmacokinetic models for CBD and VPA were used to predict liver exposure. DILIsym simulations predicted dose-dependent ALT elevations from CBD treatment and this was predominantly driven by ROS production from the parent molecule. DILIsym also predicted VPA treatment to cause ALT elevations which were transient when mitochondrial biogenesis was incorporated into the model. Contrary to the clinical experience, simulation of 2 weeks treatment with VPA prior to introduction of CBD treatment did not predict an increase of the incidence of ALT elevations relative to CBD treatment alone. We conclude that the marked increased incidence of CBD-associated ALT elevations in patients already receiving VPA is unlikely to involve the three major mechanisms of direct hepatotoxicity.

  PublisherDOI

Recent grants

• Software for Predicting Liver Injury from Biologics Drug Candidates Using Data from a Human Liver Microphysiology System

  NIH · $251k · 2021–2022

Frequent coauthors

• Scott Q. Siler

  88 shared

• Paul B. Watkins

  GTx (United States)

  83 shared

• Yuching Yang

  United States Food and Drug Administration

  55 shared

• Diane Longo

  Simulations Plus (United States)

  53 shared

• A. Sangiovanni

  49 shared

• Jeffrey L. Woodhead

  Simulations Plus (United States)

  45 shared

• Castro Valley

  Sanofi (Mexico)

  28 shared

• Ers-Squibb Roche

  Toray Industries, Inc. (Japan)

  28 shared

Labs

• Sensory Development LabPI