PK and PK / PD Modeling of Bcl2 Inhibitor S65487 in Patients With AML and Investigation of Nonlinearity With Microdosing
CPT Pharmacometrics & Systems Pharmacology June 17, 2026 Chloé Burlot, François Riglet, Mathilde Romagnoli et al.
S65487, a drug targeting the Bcl2/Bim protein complex implicated in cancer cell survival, was studied using pharmacokinetic/pharmacodynamic modeling. At a 1200 mg dose, simulations predicted a 97.6% maximum reduction in the formation of the Bcl2/Bim complex. A microdose study in healthy volunteers showed substantially different pharmacokinetic parameters compared to therapeutic doses in cancer patients, indicating slightly nonlinear drug behavior. The most plausible explanation was nonlinearity in drug disposition, modeled via a Michaelis-Menten approximation of target-mediated drug disposition. This optimized model reduced the discrepancy in describing microdose exposure from 5-fold to 1-fold, without affecting therapeutic dose descriptions, enabling better extrapolation from microdose to therapeutic dose results.