Preclinical Development – Biomolecular
2019 PharmSci 360
This presentation will provide a case study on QSP model development for a hUGT1A1-modRNA (a modified messenger RNA) lipid nanoparticle formulation to restore hepatic expression of UGT1A1 in Crigler-Najjar Type 1 patients. The QSP model was developed to support translation from preclinical to first-in-human studies. The QSP model was calibrated to plasma and liver mRNA, and total serum bilirubin in Gunn rats, an animal model of CN1. This QSP model adequately captured the observed plasma and liver biomarker behavior across a range of doses and dose regimens in Gunn rats. First-in-human dose projections made using the translated model indicated that 0.5 mg/kg Q4W dose should provide a clinically meaningful and sustained reduction of >5 mg/dL in total bilirubin levels.