Pharmacogenomic Contribution to the Biotransformation of Trihexyphenidyl and Development of a Precision Dosing Model for Children with Dystonia and Cerebral Palsy - Project Summary The goal of this 5-year K23 proposal is to support Dr. Gelineau-Morel as she becomes an independent investigator in model-informed precision dosing to facilitate clinical trials for children with cerebral palsy (CP), and especially dystonia (DCP). DCP is a movement disorder with a similar incidence to Parkinson’s Disease (1 in 1000) and is the greatest determinant of functional impairment in children with CP. Yet, there are no FDA- approved treatments, and even off-label treatments are minimally effective. Trihexyphenidyl (THP), a racemic mixture of R and S enantiomers, was effective for DCP in a clinical trial, but some participants had treatment- limiting side effects likely due to supratherapeutic exposure to THP or its enantiomers, supporting the need for precision dosing to standardize exposures. In fact, the CP community recently named identifying new and effective treatments to be their top research priority in DCP. This aligns with the NICHD/NINDS strategic plan for CP research which recommends improved precision treatments. Dr. Gelineau-Morel is ideally positioned to address this need as a child neurologist and movement disorder specialist with fellowship training in clinical pharmacology. This career development proposal (CDP) will expand Dr. Gelineau-Morel's skillset with additional training to systematically investigate pharmacogenetic sources of variability in drug exposure and develop model-informed precision dosing recommendations for exposure-controlled clinical trials. The CDP has the following objectives: 1) Develop expertise in quantifying pharmacogenomic contribution to drug exposure, 2) Become skilled in physiologically based pharmacokinetic (PBPK) modeling, 3) Gain knowledge of clinical trial design. The CDP will be facilitated through structured mentoring, didactics, and experiential training, and applied to a research plan quantifying the contribution of CYP2D6 and CYP2C19 to the biotransformation of trihexyphenidyl and developing a PBPK model. The research study has these aims: 1) Determine the impact of CYP2D6 and CYP2C19 genotype on exposure to R-THP and S-THP 2) Develop a pediatric PBPK model to simulate exposures to THP, R-THP, and S-THP based on individual’s pharmacogenotype, age, weight, and sex and 3) Establish the feasibility of a future exposure-controlled clinical trial of THP in DCP. Study results could also justify an investigational new drug application for R-THP, to maximize therapeutic benefit while minimizing side effects. Dr. Gelineau-Morel's career development and research plan will take place in the ideal environment with a large, tertiary care, academic children’s hospital, a pediatric research institute, and the Frontiers CTSI. She will be mentored by international experts in pharmacogenomics and drug biotransformation, PBPK modeling, and clinical trials. Upon completion of this K23, Dr. Gelineau-Morel will have the necessary skills and expertise to become a leader in precision neurotherapeutics and complete an R01 application for an exposure-controlled clinical trial in DCP.
