PII-045 - USE OF A POPULATION PHARMACOKINETIC MODELLING AND SIMULATION APPROACH TO IDENTIFY FLAT DOSES OF DOMVANALIMAB IN PHASE 3 STUDIES.

A. Chaturvedula¹, K. Liao², M. Zhao³, B. Agoram²; ¹Pumas-AI Inc., Centreville, VA, USA, ²Arcus Biosciences, Hayward, CA, USA, ³Gilead Sciences, Foster City, CA, USA.

Background: Domvanalimab is an Fc-silent humanised IgG1 mAb that blocks the interaction of TIGIT with CD112 and CD155, reducing inhibition of T cells and NK cells and, thereby, promoting antitumour activity. Our objective was to develop a population pharmacokinetics (PK) model of domvanalimab and derive flat doses to employ in future clinical studies.

Methods: PK and covariate data were pooled from two ongoing clinical studies (AB154CSP0001 & ARC-7), where domvanalimab is being tested as a monotherapy and in combination with zimberelimab, a PD-1 antibody, at dosing frequencies of every 2-4 weeks, and after weight-based and flat dosing. The overall dose range of domvanalimab was 0.5-20 mg/kg. Population PK modeling was conducted using mixed effects methodology using NONMEM, v7.5. Simulations in a virtual population were conducted and PK parameters were compared between weight-based and flat doses on simulated profiles after Cycle 1 and steady state.

Results: The analysis included data from a total of 111 cancer patients. A two-compartment model with weight as covariate on clearance and central volume of distribution was selected as the final model. Clearance, central volume, intercompartmental clearance and peripheral volume were estimated to be 0.26 L/d, 3.72 L, 1.33 L/d and 3.55 L, respectively. Simulations indicated that the overall difference in geometric means of all summary exposure measures between the weight based and flat dose regimens was < 1% when comparing 1200 mg to 15 mg/kg Q3W, and 1600 mg to 20 mg/kg Q4W regimens.

Conclusion: Population PK model-based simulations indicate that flat doses of 1200 mg Q3W and 1600 mg Q4W will result in similar exposure to 15 mg/kg Q3W and 20 mg/kg Q4W, respectively. These flat doses are recommended for future clinical trials to replace weight-based dosing.