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

Nan Wu; John A. Widness; Xiaoyu Yan; Peter Veng-Pedersen; Guohua An

doi:10.1016/j.xphs.2022.06.003

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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

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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

Nan Wu, John A. Widness, Xiaoyu Yan, Peter Veng-Pedersen and Guohua An

Journal of pharmaceutical sciences, Vol.111(9), pp.2620-2629

09/2022

DOI: 10.1016/j.xphs.2022.06.003

PMCID: PMC9391296

PMID: 35691608

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https://www.ncbi.nlm.nih.gov/pmc/articles/9391296View

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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 (kon), dissociation rate constant (koff), and internalization rate constant (kint) 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 (kdeg) 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.

Pharmacokinetic/pharmacodynamic (PK/PD) Modeling

Recombinant human erythropoietin (rhEpo) Nonlinear pharmacokinetics

Target-mediated drug disposition (TMDD)

Details

Title: Subtitle: 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
Creators: Nan Wu - University of Iowa
John A. Widness - University of Iowa
Xiaoyu Yan - School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
Peter Veng-Pedersen - University of Iowa
Guohua An - Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa city, Iowa, USA
Resource Type: Journal article
Publication Details: Journal of pharmaceutical sciences, Vol.111(9), pp.2620-2629
DOI: 10.1016/j.xphs.2022.06.003
PMID: 35691608
PMCID: PMC9391296
NLM abbreviation: J Pharm Sci
ISSN: 0022-3549
eISSN: 1520-6017
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: P01 HL046925
Language: English
Date published: 09/2022
Academic Unit: Stead Family Department of Pediatrics; Pharmaceutical Sciences and Experimental Therapeutics
Record Identifier: 9984366028502771

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