A cell-level model of pharmacodynamics-mediated drug disposition.
We aimed to develop a cell-level pharmacodynamics-mediated drug disposition (PDMDD) model to analyze in vivo systems where the PD response to a drug has an appreciable effect on the pharmacokinetics (PK). An existing cellular level model of PD stimulation was combined with the standard target-mediated drug disposition (TMDD) model and the resulting model structure was parametrically identifiable from typical in vivo PK and PD data. The PD model of the cell population was controlled by the production rate k in and elimination rate k out which could be stimulated or inhibited by the number of bound receptors on a single cell. Simulations were performed to assess the impact of single and repeated dosing on the total drug clearance. The clinical utility of the cell-level PDMDD model was demonstrated by fitting published data on the stimulatory effects of filgrastim on absolute neutrophil counts in healthy subjects. We postulated repeated dosing as a means of detecting and quantifying PDMDD as a single dose might not be sufficient to elicit the cellular response capable of altering the receptor pool to visibly affect drug disposition. In the absence of any PD effect, the model reduces down to the standard TMDD model. The applications of this model can be readily extended to include chemotherapy-induced cytopenias affecting clearance of endogenous hematopoietic growth factors, different monoclonal antibodies and immunogenicity effects on PK.
Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, USA.
Wojciech
W
Krzyzanski
Clinical Pharmacology, Modeling, and Simulation, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91320, USA. jharrold@amgen.com.
John M
JM
Harrold
Clinical Pharmacology, Modeling, and Simulation, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91320, USA.
Liviawati S
LS
Wu
Clinical Pharmacology, Modeling, and Simulation, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91320, USA.|Janssen Research & Development, Beerse, Antwerp, Belgium.
Juan Jose
JJ
Perez-Ruixo
D001692:Biological Transport; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D000069585:Filgrastim / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006401:Hematologic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017711:Nonlinear Dynamics; D011485:Protein Binding; D011955:Receptors, Drug / Q000378:metabolism*; D014018:Tissue Distribution
D006401:Hematologic Agents; D011955:Receptors, Drug; D000069585:Filgrastim
Absolute neutrophil count; Cell populations; Filgrastim; Target-mediated drug disposition