Model-informed Precision Dosing and Clinical Decision Support Initiatives to Improve Individualized Therapeutics in Children

Alexander "Sander" A. Vinks, PharmD, PhD, FCP

In studies funded by the Ohio Third Frontier and the Gerber Foundation, Vinks and a team of investigators from the Divisions of Neonatology, Pulmonary Biology, Clinical Pharmacology, Information Services, Biomedical Informatics, the Pain Management Center and Pediatric Palliative Care as well as the Clinical Mass Spectrometry Laboratory implemented a morphine individualized precision dosing tool into workflows of neonatal prescribing clinicians. The study seeks to support and improve neonatal pain management by implementing decision support for morphine precision dosing. The study is measuring the implementation effects by usage statistics and by comparing prescribing patterns to historical patterns from prior to implementation. The first results of the implementation of this PK / PD model-informed clinical decision support platform were recently published in Clinical Pharmacology and Therapeutics, the leading journal of the American Society of Clinical Pharmacology and Therapeutics (ASCPT).

Min Dong, PhD

Dong works with investigators in the Division of Hematology on precision dosing studies of hydroxyurea in patients with sickle cell anemia (SCA). Currently two ongoing prospective trials are: Therapeutic Response Evaluation and Adherence Trial (TREAT), and the hydroxyurea optimization through precision study (HOPS). Another initiative focuses on dose optimization of hydroxyurea in children after total pancreatectomy with islet auto-transplantation (TPIAT) with investigators from the Pancreas Care Center. Dong continues to provide pharmacometric services in support of multiple research projects in collaboration with investigators in the Divisions of Anesthesiology, Research in Patient Services, and Audiology. She is also a leader in the Cincinnati Pharmacometrics Center of Excellence program providing high level pharmacometric expertise for pediatric study design optimization, clinical trial simulation, pediatric dose selection optimization, and protocol development for pharmacokinetic (PK) and pharmacodynamic (PD) studies for FDA submission by outside sponsors.

Tomoyuki Mizuno, PhD

Mizuno works with multiple clinical teams on the development and implementation of pharmacokinetics and pharmacodynamics (PK / PD) model-informed precision dosing (MIPD) strategies in neonates, infants and children including critically ill patients. The published results are in a series of manuscripts on the MIPD sirolimus. One of the most recent is on related pediatric patients with acute lymphoblastic leukemia (ALL) in collaboration with investigators in Cancer and Blood Diseases Institute, where the study highlights predictable within-patient fluctuations in sirolimus concentrations associated with intercurrent infection and with changes in diet. With investigators in the Division of Critical Care Medicine and the Center for Acute Care Nephrology, he was instrumental in the population PK modeling of milrinone in infants with or without kidney injury (AKI) after cardiac surgery. This study developed age-appropriate milrinone dosing regimens in infants to guide initial milrinone therapy based on the AKI status. A most recent initiative is the PK / PD modeling of buprenorphine in newborns treated for neonatal abstinence syndrome (NAS) in collaboration with investigators from the Divisions of Neonatology and Pulmonary Biology. The study will develop a mechanism- and physiology-based PK / PD model to individualize buprenorphine dosing regimens in newborns to improve treatment outcome in babies with NAS.

Laura Ramsey, PhD

Ramsey works closely with the Divisions of Human Genetics, Center for Autoimmune Genomics and Etiology and the Division of Child and Adolescent Psychiatry to employ pharmacogenetics approaches in clinical and translational studies. Ramsey and collaborators from the Divisions of Clinical Pharmacology and Biomedical Informatics created a webtool that informs clinicians about methotrexate pharmacokinetics for individual patients, mtxpk.org. She also works closely with the University of Cincinnati Department of Psychiatry and Behavioral Neuroscience on neuropsychiatric pharmacogenetics in pediatric patients.

NIH T32 Pediatric Clinical Pharmacology Postdoctoral Training Program

The Division of Clinical Pharmacology is proud of its fellowship program in pediatric clinical pharmacology which is one of only five sites in the U.S. with an active program supported by the National Institute of Child Health and Development (NICHD). The goal of the postdoctoral program is to train clinical investigators to assume leadership roles in improving pediatric therapeutics. Many medicines are not studied for use in newborns and children, and there are few medicines specifically developed to treat childhood diseases. Our program supports and trains fellows in applying pharmacokinetics and pharmacogenetics / genomics principles as part of study design as well as precision medicine approaches. The National Institute of Mental Health (NIMH) supported our program to pilot the training of the next generation of pediatric psychiatrists in early stage pediatric clinical trial design and PK / PD bridging studies. We actively participate in the Adult and Pediatric Clinical Pharmacology Training Network established by NICHD, and the National Institutes of General Medical Sciences (NIGMS), as a strategic initiative to increase the pool of well-trained pediatric clinical pharmacologists.

Pharmacometrics Center of Excellence

Our program experienced tremendous growth with our service offerings, increased project diversity, and client base, including in-house, biopharmaceutical, biotechnology, and specialty pharmaceutical companies seeking expertise to determine optimal clinical trial design and pharmacometrics analysis as part of pediatric investigational plans for FDA submission. Our center offers strategic clinical pharmacology consulting and pharmacometric services to help clients improve pediatric drug development and regulatory decision-making throughout the clinical development process to increase the success rate of pediatric and adult drug studies. Our team provides expertise in clinical pharmacology, PK / PD support and data analysis, model-based drug development strategies, PK / PD modeling and simulation, study design optimization, clinical trial simulation, and the development of model-informed precision dosing strategies.

Genetic Pharmacology Service and Pharmacogenomics Implementation Research Center (Precise)

Members of the division, Vinks and Ramsey co-lead the Genetic Pharmacology Service (GPS) with Tracy Glauser, MD. The GPS established in 2004 as a multidisciplinary program involving the Divisions of Human Genetics, Neurology, Clinical Pharmacology, and Research in Patient Services. This year, Glauser presented about our GPS program at the American Epilepsy Society and Ramsey presented about the program at the Epilepsy Florida Scientific meeting. This year, the GPS transitioned to improved testing and reporting platforms, enabling improved integration of the results into the medical record.

Physician Decision Support Dashboard for Monoclonal Antibodies

With support of an Academic Research Center grant, Phillip Minar, MD, and Vinks brought together a multidisciplinary team of investigators from the Inflammatory Bowel Disease Center, the Division of Clinical Pharmacology, IS and Epic, and Human Factors Engineering and Design. This team successfully completed its year one goal of implementing this first-in-class, user-friendly, and electric health record-integrated dashboard for the precision dosing of biologics such as infliximab. A plan is in place for a pilot feasibility study to start in the next fiscal year.