PII-089 - STEREOSELECTIVE METABOLISM OF TRIHEXYPHENIDYL: THE PATHWAY TO PRECISION DOSING

R. Gelineau-Morel^1,2, P. Toren³, R. Nass³, E. Boone³, W. Wang³, J. Leeder³; ¹University of Missouri- Kansas City, Kansas City, MO, USA, ²Children's Mercy Kansas City, Kansas City, MO, USA, ³Children's Mercy Kansas City.

Background: Trihexyphenidyl (THP) is an anticholinergic drug administered as a racemic mixture to treat pediatric dystonia. The R-enantiomer (R-THP) is selective for M1 and M4 receptors in the brain involved in therapeutic efficacy. The S-enantiomer (S-THP) has equal affinity for all receptor subtypes, including M3 receptors in the gastrointestinal tract and bladder that contribute to adverse effects. Despite THP demonstrating efficacy for dystonia in clinical trials, many patients experience inconsistent efficacy and adverse effects, suggesting differing exposure to R-THP and S-THP between patients. This study investigated R-THP and S-THP biotransformation to inform individualized dosing and equalize systemic exposure.

Methods: THP (2ug/ml), R-THP and S-THP (1ug/ml) were incubated with recombinant CYP enzymes. A preliminary pharmacokinetic study of THP was performed in 3 patients prescribed THP. Analysis of metabolite formation of the in vitro and in vivo samples was conducted by achiral and chiral LCMS/MS. Patients were genotyped using Sanger sequencing + ddPCR (for CYP2D6) and the PGxExpress120 OpenArray Panel (for CYP2C19) and phenotyped to normal (NM), intermediate (IM), or poor metabolizer (PM).

Results: Incubation of THP with 12 recombinant CYPs revealed metabolite formation primarily through CYP2D6, CYP2C19, and CYP3A4. Incubation of R and S-THP with these 3 CYPs produced two hydroxylated metabolites of each enantiomer, with 81% of R-THP metabolites formed through CYP2C19 and 64% of S-THP metabolites formed through CYP2D6. Two CYP2C19 IM patients had higher R-THP concentration compared to the CYP2C19 NM. The CYP2D6 PM metabolized S-THP more slowly than the NM and IM patient.

Conclusion: THP is stereoselectively metabolized, with R-THP metabolized by CYP2C19 and S-THP metabolized primarily by CYP2D6. A preliminary pharmacokinetic study showed the CYP2C19 NM had a lower R-THP concentration, potentially leading to decreased therapeutic benefit. The CYP2D6 PM metabolized S-THP more slowly than the IM and NM, increasing risk of adverse drug reactions. Completion of a genotype-stratified pharmacokinetic study will confirm the effect of pharmacogenotype on systemic exposure to THP and inform physiologically based pharmacokinetic models for individualized dosing recommendations.