Master of Science, The Ohio State University, 1979, Graduate School

Committee: Not Provided (Other) Subjects:

Doctor of Philosophy, The Ohio State University, 2024, Pharmaceutical Sciences

Immune checkpoint inhibitors (ICIs), and immunotherapy as a whole, have been the at the forefront of cancer research for the past two decades. They have revolutionized the oncology field, and their efficacy has helped cure cancer patients, not just treat them. However, for reasons unknown, only 25-45% of patients respond to treatment. Mechanisms of ICI resistance are poorly understood and there are few biomarkers available to identify patients that will respond. Two factors associated with ICI resistance are cancer cachexia-associated increases in exogenous mAb clearance (CL) and the sex-dependent differences in nuclear hormone signaling. In this dissertation, I describe novel immune-intrinsic cancer-induced fluctuations in expression of the neonatal Fc receptor (FcRn). I also determined that in mice absent FcRn:ICI binding, cachexia-associated increased ICI CL disappears, suggesting the role of this receptor in cachexia-induced elevated ICI CL. In a separate tumor model of ICI resistance, female mice were treated with anti-PD1 in combination with two structurally distinct estrogen receptor beta (ERβ) agonists – OSU-ERβ-12 and LY500307. Tumor growth was limited in the combination treatment groups, and in a dose-dependent fashion in the OSU-ERβ-12-treated mice. Splenic immunophenotyping suggests the synergistic effects of the ERβ agonists and anti-PD1 in modulating tumor growth were due to immune activation, rather than direct action on the tumor. Together, these studies advance our knowledge of immune checkpoint inhibitor resistance mechanisms and how to overcome them.

Committee: Christopher Coss (Advisor); Emanuele Cocucci (Committee Member); Thomas Mace (Committee Member); Mitch Phelps (Advisor) Subjects: Pharmaceuticals; Pharmacology

Doctor of Philosophy, Case Western Reserve University, 2024, Nutrition

Drug resistance in both cancer and infectious disease is a major driver of mortality across the globe. In infectious disease, the emergence of antimicrobial resistance (AMR) outpaces our ability to develop novel drugs, and within-host evolution confounds the use of previously effective drugs during the course of treatment. In cancer, while targeted therapies have improved outcomes for some, many patients continue to face metastatic, drug-resistant disease, with limited therapeutic options available. As both disease types are driven by clonal evolution, a complementary approach to treatment that leverages tools and ideas from evolutionary biology has been beneficial. However, this evolutionary-inspired therapy has thus far been limited in its consideration of drug variation in time and space within a patient (pharmacokinetics) and variable pathogen response to drug (pharmacodynamics). In this dissertation, we describe novel computational and experimental approaches that integrate pharmacokinetics and pharmacodynamics to allow for more physically realistic models of the evolution of drug resistance. We apply these approaches to gain novel insights into drug dosing regimens and drug diffusion in tissue. In Chapters 1 and 2, we briefly review integrated pharmacokinetics and pharmacodynamics in the study of drug resistance and survey the current evidence of fitness costs to drug resistance in cancer. In Chapter 3, we developed a novel, fluorescence-based time-kill protocol for estimating drug dose-dependent death rates in bacteria. In Chapter 4, we described a software package, FEArS, that allows for efficient agent-based simulation of evolution under time-varying drug concentration. In Chapter 5, we leverage both of these methods to gain insight into why some antimicrobial treatments fail using computational modeling and simulated clinical pharmacokinetics. In Chapter 6, we use spatial agent-based modeling to examine how drug diffusion in tissue can promote tumor hetero (open full item for complete abstract)

Committee: Mark Chance (Committee Chair); Christopher McFarland (Committee Member); Jacob Scott (Advisor); Michael Hinzcewski (Committee Member); Drew Adams (Committee Member) Subjects: Bioinformatics; Biology; Biomedical Research; Biophysics

Doctor of Philosophy, The Ohio State University, 2024, Molecular Genetics

Breast cancer, predominantly characterized by hormone receptor-positive tumors, poses a significant global health concern. Aromatase inhibitors (AIs) such as anastrozole, letrozole, and exemestane have emerged as pivotal therapies for postmenopausal women, offering superior outcomes compared to conventional treatments. However, their effectiveness is hampered by notable side effects, especially Aromatase Inhibitor-Associated Arthralgia (AIAA), which profoundly impacts patient well-being and treatment compliance. Understanding the pharmacokinetics and pharmacodynamics of AIs is essential for optimizing therapeutic strategies and managing adverse effects. We hypothesized that genetic variations in drug-metabolizing enzymes and transporters could contribute to variability in plasma AI concentrations among individuals, potentially influencing the onset of side effects. AIAA, characterized by joint pain and stiffness, remains a subject of intense research, with animal models providing insights into its pathophysiology, albeit requiring further validation. In this study, we developed two simple, precise, and accurate liquid chromatography-mass spectrometry methods for quantifying letrozole and exemestane, representing nonsteroidal and steroidal AIs, respectively. These methods were subsequently applied to measure AIs concentrations in mouse plasma and tissues, allowing for the precise assessment of drug pharmacokinetics across different mouse strains. Various interconnected approaches using in silico, in vitro, and in vivo models revealed intricate interaction of AIs and OATP1B-type transporters. A mouse model was established to further simulate AIAA and investigate the role of transporters in arthralgia development. Lastly, we validated a biomarker that could potentially serve to identify patients with breast cancer who are at risk of AIAA development. This biomarker reflects the activity of a transporter involved in the elimination of AIs and holds promise for indivi (open full item for complete abstract)

Committee: Shuiying Hu (Advisor); Alex Sparreboom (Advisor) Subjects: Pharmacology

MS, University of Cincinnati, 2024, Medicine: Clinical and Translational Research

Background: Pediatric hematopoietic stem cell transplant (HSCT) patients are at risk of developing both sepsis and altered kidney function. Cefepime is used for empiric coverage post-HSCT and requires dose adjustment based on kidney function. Cefepime's anti-microbial effect is determined by the time free concentrations exceed bacterial minimum inhibitory concentration (MIC). Serum creatinine (SCr) is routinely used to estimate glomerular filtration rate (eGFR) but varies with muscle mass, which can be significantly lower in HSCT patients, making SCr an inaccurate kidney function biomarker. Cystatin C (CysC) eGFR is independent of muscle mass, though steroid use increases CysC. Objective: To investigate which method of estimating GFR (SCr, CysC, combined) best predicts cefepime clearance, to explore additional predictors of cefepime clearance, and to describe how eGFR impacts cefepime pharmacokinetic/pharmacodynamic (PK/PD) target attainment in pediatric HSCT patients. Study Design: Patients admitted to the pediatric HSCT unit who received ≥2 cefepime doses were prospectively enrolled. We measured total cefepime peak/trough concentrations between the 2nd-4th cefepime doses and measured SCr and CysC if they were not already obtained clinically within 24h of the cefepime samples. eGFRs were calculated with Chronic Kidney Disease in Children U25 equations. Bayesian estimates of cefepime clearance were determined with a pediatric cefepime PK model (Shoji, 2016) and PK software MwPharm++. Simple linear regression was used to compare cefepime clearance normalized to body surface area (BSA) to BSA-normalized SCr-, CysC-, and SCr-/CysC-eGFRs, while multiple linear regression was used to account for additional predictors of cefepime clearance. For target attainment, we assessed the percentage of time free cefepime concentrations exceeded 1x MIC (%fT≥1x MIC) and 4x MIC (%fT≥4x MIC) using a susceptibility breakpoint of 8 mg/L for P. aeruginosa. Results: W (open full item for complete abstract)

Committee: Patrick Ryan Ph.D. (Committee Chair); Sonya Tang Girdwood M.D. Ph.D. (Committee Member); Lin Fei Ph.D. (Committee Member); Stefanie Benoit M.D. M.P.H. (Committee Member) Subjects: Pharmacology

PhD, University of Cincinnati, 2024, Medicine: Biomedical Informatics

One in six children and adolescents have a diagnosed mental health disorder in the United States. Anxiety and depression, which affect approximately 6.3 million youth, are among the most diagnosed disorders. These illnesses are frequently comorbid and are associated with functional impairment and reduced quality of life across the lifespan. Patients often benefit from a combination of psychopharmacologic and psychotherapeutic interventions, yet there is significant interindividual variability in treatment outcomes. Identifying factors that contribute to this variation in mental health treatment outcomes is vital to developing tools that can benefit children and adolescents. Electronic health record systems contain extensive medical and health data that can be coupled with predictive modeling approaches to yield insights into improving treatment outcomes. The development of diagnostic and prognostic tools in psychiatry, however, especially in pediatric populations, has lagged behind other specialties until recently. Utilization of computational and data-driven methodologies presents the opportunity to advance the field of precision psychiatry for pediatric patients. This dissertation describes the development of predictive models using electronic health record data from the largest pediatric inpatient mental health facility in the United States. The overarching objective was to improve mental health treatment outcomes for children and adolescents, which was addressed through the application of pharmacometric modeling and machine learning approaches. First, population pharmacokinetic models were developed for two commonly prescribed selective serotonin reuptake inhibitors, escitalopram and sertraline. These models were developed using opportunistic sampling of remnant blood specimens from psychiatrically hospitalized patients. We were able to quantify the impact of CYP2C19, the enzyme primarily responsible for escitalopram and sertraline metabolism, on t (open full item for complete abstract)

Committee: Laura Ramsey Ph.D. (Committee Chair); Tracy Glauser M.D. (Committee Member); Jeffery Strawn M.D. (Committee Member); Judith Dexheimer Ph.D. (Committee Chair) Subjects: Mental Health

PhD, University of Cincinnati, 2023, Medicine: Molecular, Cellular and Biochemical Pharmacology

Tacrolimus, the most common immunosuppressant for organ transplant, has a narrow therapeutic range and is metabolized by CYP3A4/5. Up to 50% of the variability in tacrolimus exposure is explained by variants in the gene CYP3A5. Given equivalent doses, CYP3A5 expressers (*1 allele carriers) demonstrate faster tacrolimus metabolism than non-expressers. In chapter 1, we describe the effect of CYP3A5 gene, age, and concomitant fluconazole on the tacrolimus concentration. We hypothesize that CYP3A5 expressers will need more dose adjustments compared to CYP3A5 non-expressers in the 8 weeks following tacrolimus initiation. Our aim is to study pediatric patients within the first 8 weeks after kidney transplant to examine the effect of CYP3A5 genotype and other clinical factors (i.e., age and fluconazole) on tacrolimus trough concentrations and TDM outcomes. We analyzed the electronic health records of 93 patients. Banked DNA was collected, and genotyping was performed for CYP3A5. Included patients received a kidney transplant between Jan 2010 to April 2021. The tacrolimus target range was 10-15 ng/mL in the first four weeks and 7-10 ng/mL in the next four weeks. We found that CYP3A5 expressers (n=21) had fewer measurements in range than non-expressers (n=72), (32.4% vs 39.6%, P=0.029). Expressers had more dose adjustments (8 vs 6, p=0.0234), and they needed more than 170% of the required daily dose compared to the non-expressers. The concentration/dose (C0/D) ratio was influenced by age and concomitant fluconazole (p=0.0003, P=0.034, respectively). In chapter 2, our aim is to study the association between tacrolimus concentration and toxicity in the first 8 weeks after tacrolimus initiation in pediatric kidney transplant. We hypothesize that the trough concentration of tacrolimus is associated with its toxicity. Adverse reactions to tacrolimus present as CNS toxicity, gastrointestinal toxicity, and other toxicities like muscle cramps, edema, and rashes. A gl (open full item for complete abstract)

Committee: Laura Ramsey Ph.D. (Committee Chair); Steven Kleene Ph.D. (Committee Member); Jo El Schultz Ph.D. (Committee Member); Andrew Norman Ph.D. (Committee Member); Tomoyuki Mizuno Ph.D. (Committee Member) Subjects: Pharmacology

PhD, University of Cincinnati, 2022, Medicine: Molecular, Cellular and Biochemical Pharmacology

Sickle cell anemia (SCA) is a devastating inherited blood disorder, affecting 100,000 Americans and millions across the world. Without treatment, SCA results in tremendous morbidity and early mortality. Hydroxyurea is the primary and most well-established pharmacologic therapy with proven benefits to ameliorate the clinical course of SCA, primarily due to its ability to increase the expression of fetal hemoglobin (HbF), which prevents sickling of red blood cells. The optimal induction of HbF depends upon selection and maintenance of the proper dose that maximizes benefits and minimizes toxicity. Due to the significant interpatient variability in hydroxyurea pharmacokinetics, pharmacodynamics, and dosing, most patients treated with hydroxyurea receive suboptimal doses and have only modest treatment responses. In this dissertation work, we recognized this variability and using a precision medicine approach, developed and prospectively evaluated an individualized dosing model for children with SCA, designed to optimize the hydroxyurea dose and clinical response. We utilized novel laboratory methods and a sparse sampling strategy requiring only 10 microliters of blood collected 15 minutes, 60 minutes, and 180 minutes after a test dose. We used Bayesian adaptive control to estimate hydroxyurea exposure and to select an individual, optimal starting dose. This dosing strategy resulted in HbF responses greater than 30-40%, levels beyond what is achieved with traditional weight-based dosing and trial and error dose escalation. This dissertation provides proof of principle that precision dosing of hydroxyurea is not only feasible but also highly efficacious for children with SCA, producing clinical results rivaling those of the highly publicized curative gene therapy approaches. This dosing strategy, if widely implemented, has the potential to change the treatment paradigm of hydroxyurea therapy and improve outcomes for the millions of SCA patients across the world. In (open full item for complete abstract)

Committee: Russell Ware MD PhD (Committee Member); Charles Quinn (Committee Member); Hong-Sheng Wang Ph.D. (Committee Member); Alexander Vinks Pharm.D. (Committee Member); Jo El Schultz Ph.D. (Committee Member) Subjects: Pharmacology

Doctor of Philosophy, The Ohio State University, 2022, Pharmaceutical Sciences

Tyrosine kinase inhibitors (TKIs) are a class of targeted cancer therapeutics that have revolutionized the treatment of cancer. Despite having favorable therapeutic outcomes for treatment of various diseases, TKIs have highly variable interindividual pharmacokinetics and unexpected toxicities. TKI-related adverse events not only compromise the quality of care for cancer patients, but also reduces dose intensity and at times lead to treatment discontinuation which is of concern because drug exposure has shown to be related to therapeutic efficacy. Additionally, given the large number of drugs taken by the targeted population of cancer patients, drug-drug interactions (DDIs) pose a serious threat to severe adverse events. In this dissertation is a compilation of studies aimed at improving the strategy of investigating the interaction of TKIs with drug membrane transporters, elucidating the mechanisms of their transporter-mediated DDIs, and investigating TKIs as both victims and perpetrators of transporter function. More specifically, we focus on gilteritinib, a novel best-in class, FDA-approved TKI for the treatment of relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) as a monotherapy. Gilteritinib has shown superior success over standard conventional cytotoxic chemotherapy, however the pharmacokinetics of gilteritinib is characterized by high variability and patients often experience severe adverse events resulting in dose reduction or discontinuation. Currently, gilteritinib is undergoing further clinical investigation with other agents, but unfortunately, current data on its pharmacokinetic profile remains scarce, making it hard to predict potential DDIs. The biggest challenge for investigating TKIs is that the role of drug membrane transporters in TKI disposition is poorly understood, and well-designed studies are rarely conducted to determine if TKIs are substrates or inhibitors for major transporters. Moreover, the transporter-mediated drug-dru (open full item for complete abstract)

Committee: Sharyn Baker (Advisor); Alex Sparreboom (Committee Member); Christopher Coss (Committee Member); Kari Hoyt (Committee Member) Subjects: Oncology; Pharmaceuticals; Pharmacy Sciences

PhD, University of Cincinnati, 2021, Medicine: Molecular, Cellular and Biochemical Pharmacology

Methotrexate (MTX) is an old drug with many uses. At high doses (>0.5g/m2), MTX is a folate analog and anti-metabolite that was designed to perturb the folate pathway and cease cancerous cell growth by inhibiting the dihydrofolate reductase enzyme thereby draining the cells of necessary tetrahydrofolate needed for purine and pyrimidine biosynthesis and one-carbon metabolism. At low does (5 to 25 mg/m2), MTX is a disease modifying anti-rheumatic drug that modulates both immune and inflammatory pathways to achieve its therapeutic efficacy in patients with autoimmune disorders. The major caveat with the clinical uses of MTX is its well-documented, significant interindividual pharmacokinetic (PK) variability. Such variability can have a tremendous negative effect on the therapeutic response and toxicity to MTX. Thus, identifying predictors of response will help clinicians optimize treatment. In Chapter 1, we describe the impact of SLCO1B1, a liver transporter responsible for hepatic uptake of MTX, on low dose MTX PK and therapeutic response to a murine model of arthritis. We used animal models capable of recapitulating two common SLCO1B1 haplotypes, 1) the SLCO1B1*5 (human decreased function, *5) allele and 2) the SLCO1B1*14 (human increased function, *14) allele. We determined that mice lacking the ortholog of SLCO1B1, Slco1b2, displayed significantly reduced MTX clearance, higher MTX exposure, and less arthritis when compared to wildtype (WT) mice treated with the same dose. Then, using Slco1b2-guided pharmacogenetic (PGx) dose reductions for knockout (KO) and heterozygous (HET) mice, we were able to produce equivalent MTX exposure and similar efficacy to that of WT mice. Conversely, transgenic (TGx) mice expressing the human increased function *14 allele displayed significantly faster MTX clearance and decreased MTX exposure compared to TGx mice expressing the human WT *1a allele. SLCO1B1-guided PGx dose escalation in the *14 mice was able to produce equivalent MTX (open full item for complete abstract)

Committee: Laura Ramsey Ph.D. (Committee Chair); Terry Kirley Ph.D. (Committee Member); Sherry Thornton (Committee Member); Andrew Norman Ph.D. (Committee Member); Tomoyuki Mizuno (Committee Member) Subjects: Pharmacology

MS, University of Cincinnati, 2021, Medicine: Clinical and Translational Research

Background: Antibodies to infliximab (ATIs) are associated with secondary loss of response (LOR) and can constitute a risk for drug reactions. Limited studies have associated ATIs with increased infliximab clearance. We aimed to assess the impact of ATIs on infliximab clearance and LoR during the first year of therapy in a real-world Crohn disease (CD) cohort. Methods: This multicenter prospective cohort collected peak and trough serum infliximab/ATI concentrations during the first year of infliximab therapy. Clinical remission (CR) was defined as a weighted Pediatric CD Activity Index (wPCDAI) <12.5 without corticosteroids. LoR was defined as wPCDAI =12.5 for =2 infusions when previously in CR. Infliximab clearance was estimated using data from 660 infusions and compared between pre-ATI, during ATI, and following ATI resolution by MANOVA. Optimal cut off for ATI resolution was determined by receiver operating characteristic curves. Results: ATIs were detected in 68% (53/78) patients (range of 23-1828 ng/mL), with 26% (14/53) ATI >200 ng/mL. Median clearance in ATI+ was 0.0111 L/h compared to 0.0094 L/h with absent ATI (p<0.001). Among ATI+ patients, those with LoR had accelerated CL compared to patients without LoR (0.0145L/h vs. 0.0100L/h; p<0.001). A maximum ATI level of =99 ng/mL predicted ATI resolution (AUROC 0.80 [95% CI 0.64-0.96]; sensitivity 75%; specificity 70%). Conclusions: In this real-world cohort, ATIs as low as 23 ng/mL were shown to impact drug clearance. These data support active management for even low-level ATI to improve infliximab clearance and prevent LOR.

Committee: Scott Langevin Ph.D. (Committee Chair); Phillip Minar (Committee Member); Nicholas Ollberding (Committee Member) Subjects: Surgery

PhD, University of Cincinnati, 2020, Medicine: Molecular, Cellular and Biochemical Pharmacology

Despite decades of research, there is still no FDA approved treatment for cocaine use disorders. The National Institute of Drug Abuse (NIDA) has deemed the development of new therapies to treat cocaine use disorders a top priority. The pharmacology of cocaine is well understood, however targeting the dopamine system has proved to be unsuccessful. Therefore, immunotherapies such as monoclonal antibodies, mAb, that target cocaine directly have the potential to be a great success. Our lab has developed a humanized anti-cocaine monoclonal antibody, known as h2E2, for the treatment of cocaine use disorders. Preclinical studies have shown that h2E2 sequesters cocaine into the plasma compartment and prevents cocaine from distributing to the brain. By keeping cocaine out of the brain, cocaine is unable to bind to monoamine transporters and exert its effects.

Committee: Andrew Norman Ph.D. (Committee Chair); Pankaj Desai Ph.D. (Committee Member); Terry Kirley Ph.D. (Committee Member); Sarah Pixley Ph.D. (Committee Member); Hong-Sheng Wang Ph.D. (Committee Member) Subjects: Pharmacology

Doctor of Philosophy, The Ohio State University, 2020, Pharmaceutical Sciences

Membrane transporters are integral proteins contributing to the cellular integrity of all tissue and cell types. The solute carrier superfamily represents the second largest family of membrane proteins, encoding for over 400 transport proteins that collectively, play a pivotal role in cellular homeostasis, including the transport of essential nutrients or ions and the removal of toxic by-products. Moreover, membrane transporters are major contributors to the pharmacokinetics of therapeutic drugs, and the tissue specific expression of uptake transporters can serve as initiating mechanisms that govern a drug's pharmacodynamic properties (e.g., efficacy and toxicity). Here, we demonstrate that the sub-family of organic cation transporters are critical mediators initiating the debilitating toxicity profiles of chemotherapeutic agents, and that the targeting of these transporters can be exploited clinically to afford protection against injury in healthy tissues without compromising therapeutic benefits.

Committee: Alex Sparreboom PhD (Advisor); Shuiying Hu PhD (Advisor); Cynthia Carnes PharmD; PhD (Committee Member); Rajgopal Govindarajan PhD (Committee Member); Maryam Lustberg MD (Committee Member); Lara Sucheston-Campbell PhD (Committee Member) Subjects: Pharmacology

Doctor of Philosophy, The Ohio State University, 2020, Nutrition Program, The Ohio State University

Cardiometabolic diseases and its risk factors (e.g. obesity, insulin resistance, dyslipidemia) remain a major public health issue in the United States. Increases in gut-derived endotoxin (i.e. metabolic endotoxemia) due to gut barrier dysfunction and gut dysbiosis are associated with cardiometabolic diseases. Endotoxin initiates Toll-like receptor 4 (TLR4)-NFκB-mediated inflammation that drives the progression of cardiometabolic diseases [e.g. obesity, nonalcoholic steatohepatitis (NASH)] through disrupting host metabolism. Despite these implications, there are no validated strategies to manage endotoxemia-associated inflammation. Green tea extract (GTE) protects against endotoxemia-TLR4-NFκB-dependent inflammation by alleviating gut barrier dysfunction. However, the effect of GTE on the hepatic metabolome in limiting TLR4-NFκB inflammation and the impact of obesity on GTE catechin bioavailability is unknown. Thus, the central hypothesis of this dissertation is that (1) GTE will restore the hepatic metabolome in association with alleviated endotoxemia-TLR4-NFκB-mediated inflammation and (2) obesity will reduce catechin bioavailability by increasing microbial biotransformation of catechins. To test this, a combination of preclinical mass spectrometry (MS)-based metabolomics studies in rodents with NASH and a clinical pharmacokinetics trial in obese and lean individuals were conducted. In the first MS-metabolomics study, high-fat (HF)-induced obese mice with NASH were treated with GTE for 8 weeks prior to assessing the hepatic metabolome. GTE in obese mice increased bile acids and bile acid metabolites that were otherwise reduced in HF-fed obese mice. Compared to obese controls, phosphatidylcholine catabolites were reduced by GTE in obese mice. The restoration of hepatic metabolites by GTE was associated with improvements in TLR4-NFκB-mediated inflammation in NASH. In the second MS-metabolomics study, wild-type (WT) and TLR4-mutant (TLR4mut) mice were fed a HF diet fo (open full item for complete abstract)

Committee: Richard Bruno PhD, RD (Advisor); Amanda Bird PhD (Committee Member); Rachel Kopec PhD (Committee Member); Yael Vodovotz PhD (Committee Member); Zhongtang Yu PhD (Committee Member) Subjects: Nutrition

Doctor of Philosophy, The Ohio State University, 2020, Pharmaceutical Sciences

Tyrosine kinase inhibitors (TKIs) represent the largest class of anti-cancer drugs. By the end of 2019, there are a total of 46 granted FDA approval for different indications, and more are currently in various stages of development. TKIs were designed to specifically target tyrosine kinases that are involved in cancer development, including tumor cell proliferation and growth, apoptosis, and promotion of angiogenesis and metastasis. As targeted chemotherapy, TKIs are designed to target specific mutated kinase or kinases involved in particular subtypes of the tumor and, thus, are expected to have a quicker response and are better tolerated. However, TKIs have their issues in the clinic. One of the significant limitations is exposure-related toxicities. Almost all TKIs have shown relatively large body surface area-irrelevant interpatient pharmacokinetic (PK) variability. Although all TKIs are cytochrome P450 3A4 (CYP3A4) substrates, the expression and function of CYP3A4 do not strongly correlate to TKI exposure for specific multi-kinase inhibitors (MKIs) like sorafenib and regorafenib. There must be other covariates that contribute to this variability. Another main concern is their interactions with crucial transporters in drug absorption, disposition, metabolism, and excretion (ADME). Cancer patients on TKIs are very likely to be on other commonly used medications like statins, which are well-accepted as substrates of hepatic organic anion transporting polypeptides (OATPs) and metformin which is a substrate of renal organic cation transporter (OCT)2 and multi-antimicrobial extrusion protein (MATE)1/2-K or other antitumor medications of which excretion is mainly mediated by transporters. The undesired TKI-transporter interactions, mostly inhibition, could eventually lead to increased systemic exposure of victim drugs and affect their local exposure and toxicity profile. In this study, we aimed to look at i) transporters involved in the disposition pathway of sorafen (open full item for complete abstract)

Committee: Alex Sparreboom (Advisor); Sharyn Baker (Committee Member); Christopher Coss (Committee Member); Kari Hoyt (Committee Member) Subjects: Pharmaceuticals

Doctor of Philosophy, The Ohio State University, 2019, Pharmacy

The nucleoside analog cytarabine (Ara-C) is among the most effective and widely prescribed anticancer agents, but its clinical use is associated with unpredictable pharmacodynamic efficacy profiles, and the agent is liable to drug-drug interactions. Due to its hydrophilic nature, Ara-C requires functional transporters to enter cells. Despite >20 years of clinical use, the transporter(s) contributing to Ara-C disposition remain poorly understood. Recently, we reported that Ara-C is a substrate of OCTN1 using overexpression models. Here, we explored the regulation of this nucleoside analog transporter, OCTN1, its impact in the context of AML (Chapter 2), and the characterization of this transporter using in vivo models (Chapter 3). Chapter 1 focuses on introducing the disease state of Acute Myeloid Leukemia (AML) and the many factors contributing to treatment failure in patients. Of the many causes, we and others in the field have highlighted the transport of nucleoside analog as a main contributor to treatment failure. More recently, we have provided evidence of a nucleoside analog transport system, OCTN1, which plays a role in transporting a component of the first-line regimen, Ara-C, used in AML patients. In order to better understand the regulation of this transport system, we explored how epigenetic regulation, specifically DNA methylation, can affect transporter expression. Chapter 2 focuses on the regulation of OCTN1 and its impact in facilitating Ara-C accumulation within AML cells. First, we characterize the uptake and the sensitivities of AML cell lines to first-line component, Ara-C. Using AML cell lines, the uptake of Ara-C (1 µM; 15 min) varied 6-fold (17-101 pmol/mg) and was highly sensitive to the classical nucleoside transport inhibitor, NBMPR. Among other AML-directed drugs evaluated, we found that the anthracyclines, daunorubicin, and idarubicin, inhibited Ara-C uptake in a concentration-dependent manner (P<0.05). In contrast, exposure to the (open full item for complete abstract)

Committee: Sharyn Baker PharmD, PhD (Advisor); Alex Sparreboom PhD (Advisor); Cynthia Carnes PharmD, PhD (Committee Member); Christopher Coss PhD (Committee Member); Abhay Satoskar MD, PhD (Other) Subjects: Pharmaceuticals; Pharmacology; Pharmacy Sciences

PhD, University of Cincinnati, 2019, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics

High-grade gliomas (HGGs) are among the most infiltrative primary malignant brain tumors with a median survival ranging from only 15 months to five years. Current standard of care includes surgical resection, followed by adjuvant radiation and chemotherapy with temozolomide. Unfortunately, the disease recurs in almost all patients with fewer therapeutic options available thereafter. Therefore, novel HGG-specific targets and, more importantly, ligands for such targets are urgently needed. Based on the discovery that estrogen synthase `aromatase' is overexpressed in HGGs, aromatase inhibitor, letrozole, is being investigated in pre-clinical models as a novel agent against this malignancy. Employing microdialysis, in previous studies we have shown that letrozole easily crosses the blood-brain and the blood-tumor barriers. To facilitate clinical translation of these findings, here, we first conducted a comprehensive investigation of the systemic and brain pharmacokinetics of letrozole in rodents. Female and male jugular-vein cannulated (JVC) Sprague-Dawley rats were employed for this study. Both single/multiple doses of letrozole (4 mg/kg; IP) were administered and intracerebral microdialysis was performed for brain extracellular fluid (ECF) sampling. Simultaneous serial blood collection facilitated plasma pharmacokinetic determination. Essentially, marked gender-specific differences were observed in letrozole pharmacokinetics. Letrozole clearance was much slower in female rats resulting in markedly higher plasma and brain concentrations. At steady state, plasma AUC0-24 was 103.0 and 24.8 µg*h/ml and brain ECF AUC0-12 was 24.0 and 4.8 µg*h/ml in female and male rats, respectively. Given that temozolomide is the current standard of care and that letrozole will need to be clinically investigated in combination with this agent, we then discerned any potential pharmacokinetic interactions between letrozole and temozolomide in JVC rats. Microdialysis wa (open full item for complete abstract)

Committee: Pankaj Desai Ph.D. (Committee Chair); Biplab DasGupta Ph.D. (Committee Member); Joan Garrett Ph.D. (Committee Member); Gary Gudelsky Ph.D. (Committee Member); Georg Weber M.D. (Committee Member) Subjects: Pharmaceuticals

PhD, University of Cincinnati, 2018, Medicine: Epidemiology (Environmental Health)

Introduction Organ transplantation is the preferred treatment for many end-stage organ diseases. However, lifelong immunosuppression is required to prevent the risk of rejection. Tacrolimus is the most prescribed immunosuppressant following transplantation but has a complex pharmacokinetic (PK) profile, significant inter-individual variability, and a narrow therapeutic index, signifying that the threshold between efficacy and toxicity is relatively small. Therefore, therapeutic drug monitoring is required to ensure adequate efficacy and safety. Many factors, including organ donor and recipient genotypes and other clinical variables have been associated with changes in tacrolimus PK. Guidelines recommend genotyping kidney transplant recipients to assist in dosing strategies but mention that there is a lack of data to make the same recommendation in liver transplant recipients. This is of particular importance, since liver transplant recipients retain their own gut and genotype but inherit the liver donor's genotype, making the role of liver donor genotype of particular interest. In addition, novel drug formulations have been released, extending the dosing interval from twice daily to once daily, further complicating clinical use and dosing strategies. For these reasons, additional guidance for clinicians is necessary for 1) converting between different tacrolimus formulations and 2) employing clinical and pharmacogenomic data in the evaluation of dosing strategies in liver transplant recipients. Methods To address these knowledge gaps, two studies were conducted. The first one prospectively evaluated the conversion from twice-daily innovator tacrolimus to two once-daily formulations. The second study evaluated the impact of key recipient and donor genotypes on tacrolimus PK in liver transplant recipients nested in a prospective clinical trial that evaluated bioequivalence between different tacrolimus formulations. Results Upon direct evaluation of all thre (open full item for complete abstract)

Committee: Erin Haynes Dr.P.H. (Committee Chair); Rita Alloway PharmD (Committee Member); Marepalli Rao Ph.D. (Committee Member) Subjects: Surgery

Doctor of Philosophy, The Ohio State University, 2017, Pharmaceutical Sciences

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer related deaths worldwide. While management options of early stage hepatocellular carcinoma are diverse and result in good clinical outcomes, the disease prognosis for advanced stage hepatocellular carcinoma remains poor. Sorafenib, a tyrosine kinase inhibitor, is FDA approved as the first line treatment for hepatocellular carcinoma. However sorafenib exhibits low response rates and minimal improvement in survival. This highlights the need to develop new therapies for treatment of advanced hepatocellular carcinoma. mTOR pathway is commonly activated in HCC making it an attractive target for therapy. However, the rapalogs, allosteric inhibitors of mTORC1, failed to show improved clinical outcomes. We investigated the potential use of the ATP-competitive mTOR inhibitor, INK128 for treatment of HCC. We evaluated INK128 in CD44low and CD44high HCC cell lines, and in those cell lines with acquired sorafenib resistance. CD44 was significantly increased in Huh7 HCC cells made resistant to sorafenib. Forced expression of CD44 enhanced cellular proliferation and migration, and rendered the cells more sensitive to the anti-proliferative effects of INK128. INK128 showed better anti-proliferative activity in CD44high and sorafenib resistant cells compared to CD44low cells. Moreover, a combination of INK128 and sorafenib showed improved anti-proliferative effects in CD44high HCC cells. INK128 was efficacious at reducing tumor growth in CD44high SK-Hep1 xenografts in mice when given as monotherapy or in combination with sorafenib. Our findings suggest that ATP-competitive mTOR inhibitors may be effective in treating advanced, CD44-expressing HCC patients who are insensitive or resistant to sorafenib. Next, we evaluated extracellular vesicles (EVs) as a delivery system for oligonucleotide therapy in HCC. We present a thorough analysis of the immunogenic potential of human-cell (open full item for complete abstract)

Committee: Thomas Schmittgen PhD (Advisor); Mitch Phelps PhD (Advisor); Sharyn Baker PhD (Committee Member); Jack Yalowich PhD (Committee Member) Subjects: Pharmaceuticals

PhD, University of Cincinnati, 2017, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics

Tyrosine kinase inhibitors (TKIs) imatinib and nilotinib developed as anti-cancer drugs, also appear to have anti-viral activity due to their ability to disrupt productive replication and dissemination in infected cells. Consequently, these drugs are attractive candidates for “repurposing” as anti-viral agents against potential biological threats such as variola virus, monkeypox virus, and filoviruses. However, their clinical evaluation for such purposes is impractical and/or unethical. Hence, the USFDA formulated the “Animal Rule” which permits preclinical pharmacokinetic and efficacy studies in lieu of clinical trials and allow selection of effective human dose. While extensive pre-clinical data for marketed drugs is usually available, a critical issue is that animal species/strains that are employed by virologists for the above purpose are not among those routinely employed during drug development. Thus, in order to mimic human-specific systemic exposure in such animals, a prerequisite is to conduct PK studies to aid appropriate dosing regimens. Thus, the primary focus of the dissertation was to comprehensively investigate the PK of imatinib and nilotinib in preclinical species to aid in repurposing them as antiviral medical counter measures for biological threats. As a secondary aim, we employed the PK data generated to assess whether the enriched PK data from additional animal species improved the predictive power of allometry-based inter-species scaling approaches, relative to the use of physiologically-based PK (PBPKP) modeling approaches. Single dose intravenous, oral and/or intraperitoneal PK of nilotinib and imatinib was evaluated in CAST/EiJ mice, C57BL/6 mice, prairie dogs, guinea pigs and cynomolgus monkeys. Multiple dose tolerability studies were conducted in selected species using suitable drug formulations. Marked inter-species and inter-strain variability in the PK parameters such as systemic clearance and volume of distribution and res (open full item for complete abstract)

Committee: Pankaj Desai Ph.D. (Committee Chair); Jiukuan Hao Ph.D. (Committee Member); Catherine M Sherwin Ph.D. (Committee Member); Edward Merino Ph.D. (Committee Member); Georg Weber M.D. Ph.D. (Committee Member) Subjects: Pharmaceuticals