Objectives: : AMG 193 is a small molecule, next-generation methylthioadenosine-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor in active development for treating patients with advanced methylthioadenosine phosphorylase (MTAP)-deleted solid tumors. Symmetrical dimethyl-arginine (SDMA) is a stable catabolic product of PRMT5 enzymatic activity and is a widely used biomarker to monitor PRMT5 inhibition. A sequential population pharmacokinetic/pharmacodynamic (PK/PD) model was developed with plasma SDMA as a surrogate for target engagement.
Methods: A population PK model was built to characterize AMG 193 PK profiles based on a total of 1572 plasma concentration measurements from 119 cancer patients with MTAP-deleted tumors with doses ranging from 40 mg to 1600 mg QD, or 600 mg BID. The effects of age, sex, race, and body weight on the PK parameters (central volume of distribution [Vc] and clearance [CL]) were examined in this population PK analysis. Final population PK model parameters were then used as inputs to the subsequent SDMA PD model development. A total of 91 subjects with available baseline SDMA measurements, post-dose PK and post-dose SDMA samples were included. The elimination and production of SDMA were modeled as a first-order process and a zero-order process, respectively. An indirect response PD model was used to describe the inhibition by AMG 193 on SDMA production rate. Simulations were performed based on the final PK/PD model to predict the plasma SDMA reduction from baseline following 40 mg to 1600 mg QD or 600 mg BID.
Results: The preliminary PK model with first-order absorption (absorption coefficient Ka: 0.699 hr-1) and two-compartment disposition (CL: 11.5 L/hr, Vc: 194 L, intercompartment clearance Q: 11.5 L/hr, peripheral volume of distribution Vp: 101 L) adequately characterized the AMG 193 PK profiles. A relative bioavailability term of 0.697 was used to describe the less-than-dose-proportional increase in exposure for 1600 mg QD. No significant impact of age, sex, race, or body weight on the AMG 193 PK parameters was identified in the covariate analysis. The final parameter estimates of SDMA elimination rate constant (Ksdma), maximal AMG 193-dependent inhibition (Imax), and AMG 193 concentration that produces 50% of the maximal inhibition (IC50) were 0.00743 (1/hr), 0.746 (ng/mL), and 108 (ng/mL), respectively. The Hill coefficient was fixed to 1. Simulations with the final model suggested approximately 70% and 72% reduction in SDMA from baseline at doses of 800 mg QD and 1200 mg QD, respectively.
Conclusions: The analysis showed that AMG 193 PK was not impacted by age, sex, race, and body weight. Greater SDMA inhibition was associated with greater AMG 193 exposure within the 40 mg to 1200 mg dose range. This analysis characterized the PK/PD relationship for AMG 193 and SDMA in early clinical development.
Citations: None
Keywords: Population Pharmacokinetics, AMG 193, SDMA
