IU Indianapolis ScholarWorks :: Browsing by Author "Tillman, Emma M."

Browsing by Author "Tillman, Emma M."

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A Phase I Trial of the Pharmacokinetic Interaction Between Cannabidiol and Tacrolimus
(Wiley, 2025) So, Gerald C.; Lu, Jessica Bo Li; Koyama, Sachiko; Cheng, Ying-Hua; Gisch, Debora L.; McClara, Kelsey; Dexter, Paul R.; Sharfuddin, Asif A.; Etkins, Jumar; Tillman, Emma M.; Beamon, Travis R.; Cowsert, Zachary; Stuart, Jennifer S.; Desta, Zeruesenay; Eadon, Michael T.; Medicine, School of Medicine
One in six Americans uses cannabidiol-based or cannabis-derived products. Cannabidiol is a substrate of CYP3A, but its role as a potential CYP3A inhibitor remains unclear. We hypothesized that cannabidiol would inhibit CYP3A-mediated metabolism of tacrolimus. This report is an interim analysis of an open-label, three-period, fixed-sequence, crossover study in healthy participants. Participants first received a single dose of tacrolimus 5 mg orally. After washout, participants later received cannabidiol titrated to 5 mg/kg twice daily for 14 days to reach a steady state, followed by a second single dose of tacrolimus 5 mg orally. Tacrolimus concentrations in whole blood were measured by UHPLC-MS/MS method. Pharmacokinetic parameters were calculated by noncompartmental analysis. Twelve participants completed all periods of the study. The maximum concentration (Cmax) of tacrolimus increased 4.2-fold (P < 0.0001) with cannabidiol (40.2 ± 13.5 ng/mL) compared with without cannabidiol (9.85 ± 4.63 ng/mL). The area under the concentration-vs.-time curve (AUC0-∞) increased 3.1-fold (P < 0.0001). No change in half-life (t1/2) was observed. This study demonstrates that cannabidiol increases tacrolimus exposure. Our data suggest the need for dose reduction in tacrolimus and frequent therapeutic dose monitoring in transplant patients taking cannabidiol concomitantly. Whether this observed interaction occurred due to the inhibition of CYP3A4 and/or CYP3A5 in the liver, intestine, or both, or intestinal drug transporters (e.g., p-glycoprotein) during the first-pass elimination remains to be elucidated.
A pilot study of ADRA2A genotype association with doses of dexmedetomidine for sedation in pediatric patients
(Wiley, 2022) Gallaway, Katherine A.; Skaar, Skaar; Biju, Ashwin; Slaven, James; Tillman, Emma M.
Study objective: Dexmedetomidine is titrated to achieve sedation in the pediatric and cardiovascular intensive care units (PICU and CVICU). In adults, dexmedetomidine response has been associated with an ADRA2A polymorphism (rs1800544); CC genotype is associated with an increased sedative response compared with GC and GG. To date, this has not been studied in children. Design: We conducted a pilot study to determine whether ADRA2A genotype is associated with dexmedetomidine dose in children. Measurements and main results: Forty intubated PICU or CVICU patients who received dexmedetomidine as a continuous infusion for at least 2 days were genotyped for ADRA2A with a custom-designed TaqMan® Assay. Ten (25%) subjects were wildtype (GG), 15 (37.5%) were heterozygous (GC), and 15 (37.5%) were homozygous (CC) variant. The maximum dexmedetomidine doses (mCg/kg/h) were not different between genotype groups CC (1, 0.3-1.2), GC (1, 0.3-1.3), and GG (0.8, 0.3-1.2), (p = 0.37); neither were mean dexmedetomidine doses for these respective genotype groups 0.68 (0.24-1.07), 0.72 (0.22-0.98), 0.58 (0.3-0.94), (p = 0.67). Conclusions: These findings did not confirm the results from adult studies where ADRA2A polymorphisms correlate with dexmedetomidine response, therefore highlighting the need for pediatric studies to validate PGx findings in adults prior to implementation in pediatrics.
A systematic review of dexmedetomidine pharmacology in pediatric patients
(Wiley, 2024) O'Kane, Aislinn; Quinney, Sara K.; Kinney, Emily; Bergstrom, Richard F.; Tillman, Emma M.; Medicine, School of Medicine
Dexmedetomidine is a centrally acting alpha-2 agonist used for initiation and maintenance of procedural sedation and mechanical ventilation in adult and pediatric settings. It is commonly used in both pediatric and neonatal intensive care units. Dexmedetomidine requires extensive titration, and patients can be over or under-sedated during titration, leading to adverse events such as hypotension and bradycardia, or inadequate sedation, which can result in self-extubation. There is a critical need to identify factors that contribute to variation in metabolism, clearance, and downstream targets of dexmedetomidine so that individualized pediatric dosing regimens can be developed. This review is focused on dexmedetomidine pharmacokinetics and pharmacodynamics in the pediatric population and dexmedetomidine-related pharmacogenes in both adults and children. We found that the strongest predictors of dexmedetomidine pharmacokinetics were age and size. Multiple pharmacogenes of significance have been identified, including ADRA2A, UGT2B10, UGT1A4, CYP1A2, CYP2A6, and CYP2D6. Evidence is weak for the correlation of these individual polymorphic genes with dexmedetomidine pharmacokinetics/dynamics, though there may be a polygenetic influence on pharmacologic response. This review provides a comprehensive overview of the genomic data gathered to date. We aim to summarize current pharmacologic studies regarding dexmedetomidine use and pharmacology in pediatric patients.
Correction: Nelson et al. UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation. Cancers 2021, 13, 1566
(MDPI, 2024-10-25) Nelson, Ryan S.; Seligson, Nathan D.; Bottiglieri, Sal; Carballido, Estrella; Del Cueto, Alex; Imanirad, Iman; Levine, Richard; Parker, Alexander S.; Swain, Sandra M.; Tillman, Emma M.; Hicks, J. Kevin; Pharmacology and Toxicology, School of Medicine
Cyclic Vomiting Syndrome in Pediatric Patients: A Review of Therapeutics
(Pediatric Pharmacy Association, 2022) Tillman, Emma M.; Harvath, Emily M.; Medicine, School of Medicine
Cyclic vomiting syndrome (CVS) is a functional gastrointestinal disorder that can present quite a challenge to clinicians caring for children with this complex disease. Different therapeutic interventions are recommended for prophylaxis and acute abortive therapy for a CVS attack. The aim of this review is to summarize therapeutic treatment recommendations from the 2008 North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHN) Consensus Statement on the Diagnosis and Management of Cyclic Vomiting Syndrome and discuss studies contemporary to this expert recommendation. After an extensive search of medical databases, 8 studies that evaluated therapeutic treatments for CVS were identified. Amitriptyline and cyproheptadine remain the standard of care for prophylaxis. Nutritional supplements such as carnitine and coenzyme Q10 have shown efficacy in decreasing episodes and severity in small studies with high tolerability among patients. The combination of ondansetron and sumatriptan are recommended for abortion of an acute vomiting episode, but other agents such as aprepitant and sedative agents can be considered when vomiting is refractory to initial treatments.
Development of a Multifaceted Program for Pharmacogenetics Adoption at an Academic Medical Center: Practical Considerations and Lessons Learned
(Wiley, 2024) Shugg, Tyler; Tillman, Emma M.; Breman, Amy M.; Hodge, Jennelle C.; McDonald, Christine A.; Ly, Reynold C.; Rowe, Elizabeth J.; Osei, Wilberforce; Smith, Tayler B.; Schwartz, Peter H.; Callaghan, John T.; Pratt, Victoria M.; Lynch, Sheryl; Eadon, Michael T.; Skaar, Todd C.; Medicine, School of Medicine
In 2019, Indiana University launched the Precision Health Initiative to enhance the institutional adoption of precision medicine, including pharmacogenetics (PGx) implementation, at university-affiliated practice sites across Indiana. The overarching goal of this PGx implementation program was to facilitate the sustainable adoption of genotype-guided prescribing into routine clinical care. To accomplish this goal, we pursued the following specific objectives: (i) to integrate PGx testing into existing healthcare system processes; (ii) to implement drug-gene pairs with high-level evidence and educate providers and pharmacists on established clinical management recommendations; (iii) to engage key stakeholders, including patients to optimize the return of results for PGx testing; (iv) to reduce health disparities through the targeted inclusion of underrepresented populations; (v) and to track third-party reimbursement. This tutorial details our multifaceted PGx implementation program, including descriptions of our interventions, the critical challenges faced, and the major program successes. By describing our experience, we aim to assist other clinical teams in achieving sustainable PGx implementation in their health systems.
Enhancing Pediatric Adverse Drug Reaction Documentation in the Electronic Medical Record
(Wiley, 2021-02) Tillman, Emma M.; Suppes, Sarah L.; Feldman, Keith; Goldman, Jennifer L.; Pharmacology and Toxicology, School of Medicine
Adverse drug reactions (ADRs) often go unreported or are inaccurately documented in the electronic medical recorded (EMR), even when they are severe and life-threatening. Incomplete reporting can lead to future prescribing challenges and ADR reoccurrence. The aim of this study was to evaluate the documentation of ADRs within the EMR and determine specific factors associated with appropriate and timely ADR documentation. Retrospective data were collected from a pediatric hospital system ADR reports from October 2010 to November 2018. Data included implicated medication, type, and severity of reaction, treatment location, the presence or absence of ADR documentation in the EMR alert profile within 24 hours of the ADR hospital or clinic encounter discharge, ADR identification method, and the presence or absence of pharmacovigilance oversight at the facility where the ADR was treated. A linear regression model was applied to identify factors contributing to optimal ADR documentation. A total of 3065 ADRs requiring medical care were identified. Of these, 961 ADRs (31%) did not have appropriate documentation added to the EMR alert profile prior to discharge. ADRs were documented in the EMR 87% of the time with the presence of pharmacovigilance oversight and only 61% without prospective pharmacovigilance (P < .01). Severity of ADR was not a predictor of ADR documentation in the EMR, yet the implicated medication and location of treatment did impact reporting. An active pharmacovigilance service significantly improved pediatric ADR documentation. Further work is needed to assure timely, accurate ADR documentation.
Evaluating and Mitigating Risk of Acute Kidney Injury with the Combination of Vancomycin and Piperacillin-Tazobactam in Children
(Springer, 2021-07) Tillman, Emma M.; Goldman, Jennifer L.; Medicine, School of Medicine
The antibiotic combination of vancomycin (VAN) and piperacillin-tazobactam (PTZ) has been associated with an increased risk of acute kidney injury (AKI) in both adult and pediatric patients. In this review, we highlight some of the limitations of existing pediatric studies evaluating the combination of VAN/PTZ, focusing on AKI risk in specific pediatric patient populations. We also review the variability in defining AKI in children and provide guidance to clinicians for use of prospective surveillance and stewardship in mitigating the risk of AKI in pediatric patients treated with combination of VAN/PTZ. Based on review of available pediatric studies, if the combination of VAN/PTZ is selected as an empirical antibiotic combination, it should be used in those at low risk for AKI and should be used with extreme caution in patients with additional nephrotoxic risks. Systems should be in place to monitor the use of VAN/PTZ and associated renal function in those receiving this antibiotic combination.
Implementing a pragmatic clinical trial to tailor opioids for chronic pain on behalf of the IGNITE ADOPT PGx investigators
(Wiley, 2024) Skaar, Todd C.; Myers, Rachel A.; Fillingim, Roger B.; Callaghan, John T.; Cicali, Emily; Eadon, Michael T.; Elwood, Erica N.; Ginsburg, Geoffrey S.; Lynch, Sheryl; Nguyen, Khoa A.; Obeng, Aniwaa Owusu; Park, Haesuk; Pratt, Victoria M.; Rosenman, Marc; Sadeghpour, Azita; Shuman, Saskia; Singh, Rajbir; Tillman, Emma M.; Volpi, Simona; Wiisanen, Kristin; Winterstein, Almut G.; Horowitz, Carol R.; Voora, Deepak; Orlando, Lori; Chakraborty, Hrishikesh; Van Driest, Sara; Peterson, Josh F.; Cavallari, Larisa A.; Johnson, Julie A.; Dexter, Paul R.; IGNITE Pragmatic Trials Network; Medicine, School of Medicine
Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment.
Incidence of Corrected QT Prolongation With Concomitant Methadone and Atypical Antipsychotics in Critically Ill Children
(Allen Press, 2021) Hughes, Kaitlin M.; Thorndyke, Anne; Tillman, Emma M.; Pediatrics, School of Medicine
Objective: To evaluate the safety of the combination of methadone and an atypical antipsychotic in PICU patients. Methods: This was a retrospective observational cohort pilot study in a single-center PICU in an academic children's hospital. Children 1 month to 18 years of age were included if they received methadone, were then initiated on an atypical antipsychotic (i.e., quetiapine or risperidone), and had EKG monitoring before and after medication initiation. Results: Prolongation of the corrected QT (QTc) interval occurred in 5 of the 34 included patients when an atypical antipsychotic was added to methadone. Of the 5 patients who had a prolonged QTc interval, 4 (80%) were older than 12 years and had a median weight of 91.3 kg. There were statistical differences between age and weight when comparing patients who experienced QTc prolongation, but no differences in sex, ethnicity, electrolyte deficiencies, number of additional QTc-prolonging medications, and number of additional drug-drug interactions were identified. When comparing atypical antipsychotics, 9.5% of patients receiving risperidone had a prolonged QTc interval, versus 23% of patients receiving quetiapine (p = 0.04). The net change in QTc interval after initiation of methadone was 0.19 milliseconds (IQR: -3, 15), which increased after atypical antipsychotic initiation to 4 milliseconds (IQR: -16, 15). Conclusions: Our pilot trial suggests there is no clinically significant difference in incidence of QTc prolongation with addition of atypical antipsychotics to methadone.

Browsing by Author "Tillman, Emma M."

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