A Pharmacometrics Model to Characterize a New Type of Target-Mediated Drug Disposition (TMDD) - Nonlinear Pharmacokinetics of Small-Molecule PF-07059013 Mediated By Its High-capacity Pharmacological Target Hemoglobin With Positive Cooperative Binding.

Abstract

In general, small-molecule target-mediated drug disposition (TMDD) is caused by the interaction of a drug with its high-affinity, low-capacity pharmacological target. In the current work, we developed a pharmacometrics model to characterize a new type of TMDD, where the nonlinear pharmacokinetics (PK) is mediated by a high-capacity pharmacological target with cooperative binding instead of target saturation. The model drug we used was PF-07059013, a noncovalent hemoglobin modulator that demonstrated promising preclinical efficacy to treat sickle cell disease (SCD), and showed complex nonlinear PK in mice with the fraction of unbound drug in blood (fub) decreased with an increase in PF-07059013 concentrations/doses due to the positive cooperative binding of PF-07059013 to hemoglobin. Among the various models we evaluated, the best one is a semi-mechanistic model where only drug molecules not bound to hemoglobin were allowed for elimination, with the nonlinear pharmacokinetics being captured by incorporating cooperative binding for drug molecules bound to hemoglobin. Our final model provided valuable insight on target binding-related parameters, such as the Hill coefficient γ (estimated to be 1.6), binding constant KH (estimated to be 1450 µM), and the amount of total hemoglobin Rtot (estimated to be 2.13 µmol). As the dose selection of a compound with positive cooperative binding is tricky and challenging due to the nonproportional and steep response, our model may be valuable in facilitating the rational dose regimen selection for future preclinical animal and clinical trials for PF-07059013 and other compounds whose nonlinear pharmacokinetics are caused by similar mechanisms.