Erythropoietin (EPO) is a 34-kD glycoprotein hormone mainly secreted by the kidney. Once bound with its receptors (EPO-Rs) located on erythroid progenitors specifically, EPO can stimulate the proliferation and differentiation of erythroid progenitors to promote the production of red blood cells (RBCs). In vivo mechanism studies indicated that EPO is eliminated not by liver or kidney, but substantially by bone marrow where erythroid progenitors primarily distribute. Structurally very similar to EPO, recombinant human erythropoietin (rhEPO) has been used as a major therapeutic agent for treatment of anemia in cancer patients undergoing chemotherapy. Our clinical studies showed that rhEPO pharmacokinetics (PK) were perturbed in humans undergoing 4 periods of altered marrow integrity: 1) pre-bone marrow myeloablation baseline; 2) post-ablation/pre-transplant when erythroid progenitors would be absent; 3) early post-transplant pre-engraftment when erythroid progenitors would be starting to become reestablished; and 4) late post-transplant full engraftment recovery when erythroid progenitors are fully reestablished. The nonlinear PK of rhEPO is likely due to its specific binding to limited number of EPO-Rs located on the finite, but expandable, number of bone marrow erythroid progenitors, a phenomenon known as target-mediated drug disposition (TMDD). This presentation will discuss a 2-compartment TMDD model developed in NONMEM software to quantitatively characterize the nonlinear elimination of rhEPO in all patients undergoing hematopoietic transplantation. As our model predicted, association rate constant kon is 0.0025 pM-1h-1, and the dissociation rate constant koff is 0.15 h-1. Internalization rate constant (kint) of the Epo-target complex was estimated to be 0.25 h-1. Total Epo receptor concentration (Rmax) was estimated to be 1.40 pmol/L/kg in adult subjects and 0.83 pmol/L/kg in pediatric subjects during the pre-bone marrow myeloablation baseline. After post-ablation/pre-transplant, EpoR was predicted to recover by 58% and 60% respectively during early post-transplant pre-engraftment and late post-transplant full engraftment stages for all subjects. In addition, in this population-based TMDD model, covariates, inter-individual variability and inter-occasional variability have been evaluated. Body weight was identified to be the significant covariate on clearance (CL) and volume of distribution (Vc). The allometric coefficients on Vc and CL were estimated to be 1 and 0.75, respectively. Inter-individual variability estimates on central and peripheral volume of distribution were 19%, 85% respectively. Inter-occasional variability (IOV) was added on Rmax to account for the change of Epo receptor concentration during different periods, and IOV on Rmax was estimated to be 55%. The information gained provide a more mechanistic scope for optimizing dosing strategies in rhEPO therapy.
Upon completion, participant will be able to define what TMDD is.
Upon completion, participant will be able to demonstrate r-HuEPO PK in humans following bone marrow ablation.
Upon completion, participant will be able to understand how TMDD is applied to clinical pharmacology research.