Background: Rilzabrutinib is a novel, highly selective Bruton’s tyrosine kinase (BTK) inhibitor being developed for the treatment of autoimmune and inflammatory diseases. This analysis aimed to develop a population pharmacokinetic (Pop PK) model for rilzabrutinib in healthy subjects and pemphigus patients and to assess the influence of covariates on rilzabrutinib PK. Methods: The model was developed using data pooled from six phase 1 studies in 151 healthy subjects, one phase 2 (NCT02704429) and one phase 3 (NCT03762265) studies in 106 pemphigus patients. Rilzabrutinib was given orally at single or multiple doses once or twice daily from 50 to 600 mg. PK data were analyzed using NONMEM. Weight, age, sex, ALP, AST, ALT, creatinine clearance, bilirubin, population, race, formulation, dose levels were evaluated during covariate analysis. The final model was validated by visual predictive checks and bootstrap analysis. Results: Rilzabrutinib PK was adequately described by a 2-compartment model with linear clearance and first-order absorption. Population mean (RSE%) estimates for apparent clearance, apparent central volume, and absorption rate constant were 949 L/h (6.4%), 732 L/h (8.5%), 0.6/h (2.8%), respectively. The clearance for pemphigus patients was found to be 64% lower than healthy subjects. The relative bioavailability increased with dose level, IR tablet had lower bioavailability compared to liquid formulation. Absorption rate showed a negative relationship with dose level. Conclusion: A Pop PK model was developed to characterize rilzabrutinib PK in healthy subjects and pemphigus patients. Population, formulation, and dose were identified as statistically significant covariates.
