A Full Target-Mediated Drug Disposition (TMDD) Model to Explain the Changes in Recombinant Human Erythropoietin (rhEpo) Pharmacokinetics in Patients with Different Bone Marrow Integrity Following Hematopoietic Transplantation

Abstract

Our aim was to build a mechanistic full target-mediated drug disposition (TMDD) model for rhEpo to better understand rhEpo disposition, Epo receptor (EpoR) synthesis, and degradation in hematopoietic transplant patients with four distinct bone marrow conditions. All PK data were analyzed simultaneously using the nonlinear mixed effect modeling approach with NONMEM. The final model was a two-compartmental full TMDD model, which adequately characterizes rhEpo PK in patients and provides insight into the dynamics of free EpoR, rhEpo-EpoR, and total EpoR. The model predicted association rate constant (k_on), dissociation rate constant (k_off), and internalization rate constant (k_int) were 0.0276 pM^-1h^-1, 0.647 h^-1, and 0.255h^-1, respectively, which were supported by experimental data. Also, the EpoR degradation rate constant (k_deg) was estimated to be 0.461 h^-1. EpoR production rate was estimated to be 37.5 pM/h for adults at pre-ablation baseline and 5.91 pM/h, and 4.19 pM/h in the early post-transplant post-engraftment, and late post-transplant full engraftment. Our model provides extensive information on the dynamics of free EpoR, total EpoR and rhEpo-EpoR, and proven to be more robust and can provide more physiologically relevant binding parameters than previous models.

Keywords: Pharmacokinetic/pharmacodynamic (PK/PD) Modeling; Recombinant human erythropoietin (rhEpo) Nonlinear pharmacokinetics; Target-mediated drug disposition (TMDD).