Population Pharmacokinetics of Oral Brepocitinib in Healthy Volunteers and Patients

Brepocitinib, a dual inhibitor of tyrosine kinase 2 and Janus kinase 1, is being investigated for the treatment of inflammatory autoimmune diseases. This study aimed to enhance the pharmacokinetic understanding of brepocitinib by developing a population pharmacokinetic model and identifying factors influencing drug disposition. Plasma samples from five clinical trials, involving healthy volunteers and patients with psoriasis or alopecia areata taking oral brepocitinib, were analyzed. NONMEM software was employed to create the pharmacokinetic model, testing various patient demographics as covariates.

The final model was a one-compartment model with first-order absorption. Typical values for apparent clearance and apparent volume of distribution were 18.7 L/h (78% coefficient of variation [CV]) and 136 L (60.5% CV), respectively. The drug was rapidly absorbed, with an absorption constant of 3.46 hours and an absorption lag of 0.24 hours for the oral tablet formulation. Proportional residual error was 52.7% CV in healthy volunteers and 87.5% CV in patients.

The study found that high-fat meals reduced the rate of absorption by 69.9% and the extent of absorption by 28.3%. Additionally, Asian populations exhibited 24.3% lower clearance. Nonlinear pharmacokinetics were observed at doses of 175 mg and above, with a 35.1% increase in relative bioavailability at these higher doses. However, there was insufficient data to describe this nonlinearity as a continuous function.

This initial pharmacokinetic characterization of brepocitinib provides a foundation for model-informed drug development and will support future modeling and optimization of this medication.