Population Pharmacokinetics of Quemliclustat, a Potent, Selective, and Reversible CD73 Inhibitor, in Patients with Cancer
Authors: Johnson Jordon , Linsmeier Ian , Jin Lixia , Ginn Elaine , Seitz Lisa , Chaturvedula Ayyappa 
Published: February 2025

Objectives: Quemliclustat (Q) is a potent, selective, small-molecule inhibitor of soluble and membrane-bound CD73 developed with the aim of blocking adenosine-mediated immunosuppression in the tumor microenvironment. The analysis objectives were to construct a population pharmacokinetic (Pop PK) model for Q and conduct simulations to recommend an optimal dose for a Phase 3 (Ph3) study.Methods: The PopPK analysis included data from two phase 1 studies in cancer patients (ARC-6 and ARC-9), one in healthy volunteers (HVs) (AB680CSP0001) and one phase 1b/2 study in cancer patients (AB680CSP0002 or ARC-8). Peripheral CD73 activity was determined using data from HVs and patients. An Emax model, based on the PK-pharmacodynamic (PD) relationship between Q and CD73 activity, determined the Ctrough required to achieve ≥ 90% inhibition (IC90). Model and graphical evaluations were conducted using NONMEM (v7.5) and R (v4.2.3). Selected covariates included weight, race, creatinine clearance (CrCL), AST, total bilirubin (TBIL), ECOG-PS, tumor size (TS), and dose. A full model was constructed using univariate selection to determine if a covariate improved the model fit (α=0.05). Backward elimination was performed until no further covariates could be removed without worsening model fit (α = 0.001). The stability and validity of the final model was evaluated using nonparametric bootstrapping and prediction-corrected visual predictive checks (pc-VPC). Covariate effects in the final model were evaluated using forest plots. The optimal dose, based on achieving a Ctrough above the CD73 IC90, was identified using simulated PK profiles for 50, 100 and 200 mg Q2W dosing.Results: The final dataset included 3189 PK observations from 271 patients with doses ranging from 0.1 mg-200 mg, as a single dose or every 1 or 2 weeks (QW or Q2W). The PK profile of Q was best described by a two-compartment model with both linear and non-linear clearance. The estimated linear clearance (CL) and central volume of distribution (Vd) were 0.065 L/hr and 5.18 L, respectively. Weight and CrCL were significant covariates on Vd and CL, respectively. For 100 mg Q2W, compared to the median, the Cmax,ss at the 95th percentile of the weight range was predicted to be 23% lower and 40% higher at the 5th percentile. Moderate renal impairment (RI) (CrCL of 30 mL/min), relative to median CrCL, was predicted to increase the Cmax,ss by 15% and AUCss by 77%. None of the other covariates (race, AST, TBIL, ECOG-PS, or TS) were significant. pc-VPC plots indicated no bias. PK simulations indicated 100 mg Q2W is the lowest dose yielding an average Ctrough above the CD73 IC90. Conclusions: A two-compartment model with parallel linear and nonlinear clearance adequately described the PK properties of Q in HVs and patients. No dose adjustment for weight or moderate RI is necessary based on available safety data. The overall PKPD profile of Q indicates the dose of 100 mg Q2W is an appropriate dose for Ph3 trials. Citations: [1] Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011 Jun;13(2):143-51. doi: 10.1208/s12248-011-9255-z. Epub 2011 Feb 8. PMID: 21302010; PMCID: PMC3085712.