PII-174 - PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL TO ASSESS THE IMPACT OF GENETIC VARIABILITY IN PATIENTS RECEIVING DEXMEDETOMIDINE.

A. O'Kane¹, E. Tillman², Z. Desta², R. Bergstrom², S. Quinney³; ¹Indiana University School of Medicine, Indianapolis, IN, USA, ²Indiana University, Indianapolis, IN, USA, ³School of Medicine, Indiana University, Indianapolis, IN, USA.

Background: Dexmedetomidine is a central α-2 agonist used for clinical sedation. It requires extensive titration and has a variable PK and PD profile. The objective of this study is to predict the effect of pharmacogenomic (PG) variants in drug modifying enzymes (DMEs) on dexmedetomidine pharmacokinetics (PK) using physiologically based pharmacokinetic (PBPK) modelling.

Methods: An adult PBPK model for dexmedetomidine was constructed in Simcyp V22 using in vitro metabolism data to inform clearance.1-3 The default Simcyp healthy volunteer population file was used to validate the model against data from clinical PK studies.4,5 The impact of PG variants of UGT2B10, UGT1A4, and CYP2A6 was evaluated against an EM model to identify the effect of PG on predicted to observed AUC ratio (AUCR).

Results: The AUCR for validation studies (0.7 mcg/kg/h for 24 hours, 0.34 mcg/kg/h for 24 hours, 0.17 mcg/kg/h for 12 hours and 24 hours) were within 2-fold. The AUC in a population with EM for all DMEs was 44.3 ng/ml/h (42.29-46.1) for following 24 h infusion of 0.7 mcg/kg/h. PMs of UGT2B10 or UGT2A6 had increased AUC, which was compounded in PMs of all three DMEs (Table 1).

Conclusion: To our knowledge, this is the first PBPK model to accurately predict PK of dexmedetomidine. Genetic polymorphisms in UGT2B10 and CYP2A6 may contribute to inter-individual variability in PK and response.