Radio‐labeled neutrophil kinetics

Data from three previously reported tracer kinetic studies of granulocyte disposition in normal humans 8 , 9 , 10 were used to model the neutrophil trafficking in organs. In these studies, granulocytes were isolated from whole blood, labeled with radioactive ¹¹¹In, and re‐injected to the subjects. Serial blood samples were obtained between 5 min and 48 h following administration of labeled cells. In addition, these studies used dynamic and static gamma camera imaging to record activity in the lung (chest), liver, spleen, and bone marrow (sacro‐iliac joints and lumbar spine). 8 , 9 , 10 Reported data were digitized and used in model development as described below. The percent of labeled granulocytes in blood at 13 times over 48 h postinjection were obtained from Figure 1 (normal subjects). 9 The labeled granulocytes in the lungs, liver, spleen, and bone marrow obtained from imaging analysis at various times postinjection were obtained from the references as follows: Figure 4, 8 Figure 4, 9 and Table 2. 10

Diagram of the circulatory neutrophil model. Bone marrow (BM) granulopoieses includes progenitor cell production (PC0), the proliferating progenitor cell cycle (G1, S, and G2/M), metamyelocytes (Mi), band cells (Bi), and segmented neutrophils (Si). Mature segmented neutrophils (S3) are released to the vascular space (v) and transported to the central venous pool (Sb), or undergo transendothelial migration to the interstitial space (is) to be either cleared or recycled via the lymphatic flow (dotted arrow). Granulocyte colony‐stimulating factor (G‐CSF) induced release of all stages of segmented neutrophils (Si) and band cells (Bi) is shown (arrows from cell to vascular space), and subsequent circulation to the venous blood (arrows into Sb and Bb). In the venous and arterial blood pools, circulating segmented neutrophils (Sb) exchange with marginated neutrophils (Mb). For other tissues (lung, spleen, liver, and others), neutrophils enter the local vascular space and can undergo transendothelial migration to the organ interstitial space, where they are cleared or recycled via the lymphatic system. The dashed box on the left represents G‐CSF kinetics and regulatory subsystem. Endogenous production and clearance of G‐CSF are included, as is the linear and target‐mediated disposition of administered filgrastim and pegfilgrastim. G‐CSF’s stimulatory effects on proliferation of progenitor cells (PCs) in bone marrow, maturation in bone marrow, and mobilization from bone marrow to blood and on blood margination are indicated by the dashed arrows. The complete set of model equations is provided in the Supplementary Information S1

Model parameter estimates obtained from pegfilgrastim and filgrastim studies

The remaining parameters were fixed as reported previously 7 and are listed in the Supplementary Information S3.

Abbreviation: G‐CSF, granulocyte colony‐stimulating factor.

Model predictions versus observations from a phase I clinical trial of paclitaxel plus carboplatin combination therapy. Top panels: Model predicted (line = median; shaded area = prediction interval) and measured (symbols) absolute neutrophil count (ANC) time profiles in 12 representative patients from four baseline ANC (BANC) groups (3 per group), with BANC ranges less than 3.3 ×10⁹ (first row), between 3.3 and 4.2 ×10⁹ (second row), between 4.2 and 5.9 ×10⁹ (third row), and above 5.9 ×10⁹ cells/L (fourth row). Bottom graph: Model predicted versus measured ANC values in all patients. Symbols = measurements; solid line = line of identity; dashed line = regression line