Pharmacodynamic modeling of thrombopoietin, platelet, and megakaryocyte dynamics in patients with acute myeloid leukemia undergoing dose intensive chemotherapy.
A proposed model of thrombopoietin (TPO) regulation is that of a constitutive production of TPO with circulating levels being predominately regulated by changes in platelet and megackaryocyte mass. Using a pharmacodynamic (PD) approach, the authors examined the validity of this model for patients with acute myeloid leukemia (AML) undergoing dose-intensive postinduction chemotherapy (HDT). TPO and platelet values were assayed weekly in AML patients undergoing HDT. A parsimonious dynamic model was then applied to these experimental data. The results (1) support the proposed model of TPO regulation, (2) model and quantify the effects of HDT on the megakaryocyte compartment, (3) characterize variables not amenable to direct measurement, and (4) have clinical utility as this model predicted that TPO given after HDT would not have a significant effect on platelet recovery, a finding borne out in clinical trials. This model provides information relevant to the interpretation of clinical trials of hematopoietic growth factors.
Bernstein
Steven H
SH
Division of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Jusko
William J
WJ
Krzyzanski
Wojciech
W
Nichol
Janet
J
Wetzler
Meir
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D002452:Cell Count; D003561:Cytarabine / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015255:Idarubicin / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects*; D008875:Middle Aged; D013926:Thrombopoietin / Q000378:metabolism*; D013997:Time Factors
D000970:Antineoplastic Agents; D003561:Cytarabine; D013926:Thrombopoietin; D015255:Idarubicin