173: Pharmacokinetic & Pharmacodynamic Modeling of QY201, a JAK1/TYK2 Inhibitor, in Healthy Chinese Adults

Statement of Purpose: QY201 is a JAK1/TYK2 selective inhibitor targeting inflammatory skin disease including atopic dermatitis and psoriasis. We developed a population pharmacokinetics (PK) and pharmacodynamics (PD) model using Phase I study data to characterize the PK and PD (pharmacology and safety biomarkers) of QY201 in healthy Chinese adults.

Description of Methods & Materials: Intense samplings were applied to healthy Chinese adults receiving single ascending doses (1 – 40 mg) or multiple ascending doses (3 – 30 mg, b.i.d. for 8 days) QY201 tablets. A population pharmacokinetic model for QY201 was first developed. Sequentially, pharmacodynamic models of absolute neutrophil count (ANC) as a safety marker and high sensitive C-reactive protein (hsCRP) as a pharmacological marker were modeled separately. The ANC and hsCRP data in 40 subjects from the multiple ascending dose cohorts were used in the model. However, 15 subject’s ANC data were excluded from the modeling because they had multiple consecutive ANC sampling points above their baseline during the dosing period. Demographics and laboratory test were collected as covariates.

Data & Results: 1,894 PK samples from 94 participants were involved in the analysis. PK of QY201 was best described by a 2-compartment model with a delayed first-order absorption and a first-order elimination. Typical values for QY201 oral clearance, volume of central and peripheral compartments, absorption rate and absorption lag time were 57.9 L/h, 8.04 L, 145L, 0.649 /h, and 0.14 h, respectively. The body weight was introduced using allometric scaling. No other covariates on clearance were identified. ANC and CRP were best described by indirect response models, where their decreases in production was linked to QY201 concentration. The QY201 concentration of half-maximal inhibition of ANC was more than 10-fold higher than that of hsCRP, this greater than 10-fold margin is the worst-case scenario where only the subjects with ANC decreases representing the sensitive group were in the model. These results indicating QY201’s ANC effect is modest compared with the effect of the compounds in the class. With QY201 10 mg b.i.d., the maximum hsCRP inhibition reported for Abrocitinib’s therapeutic dose (~86%) could be achieved, and the effect was saturated at higher doses.

Interpretation, Conclusion or Significance: The population PK-PD model well described the PK and pharmacology and safety biomarkers of QY201 in healthy Chinese adults. The modeling approach can inform the dose selection and predict the safety and efficacy of QY201 Phase 1b and Phase II studies in atopic dermatitis.

Disclosures: J.S., L.X.Q., and S.D.Q. are employees of E-nitiate Biopharmaceuticals (Hangzhou) Co.,Ltd. H.L. is an employee of Betta Pharmaceuticals Co.,Ltd. Z.R.R and B.J. declare no conflicts of interest.