Basic pharmacodynamic models for agents that alter production of natural cells

Basic indirect pharmacodynamic models for agents which alter the generation of natural cells based on a life-span concept are introduced. It is assume d that cells (R) are produced at a constant rate (k(in)), survive for a spe cific duration T-R, and then are lost. The rate of cell loss must equal the production rate but is delayed by T-R. A therapeutic agent can stimulate o l inhibit the production rate according to the Hill function: 1 +/- H(C(t)) where H(C(t)) contains capacity (S-max) and sensitivity (SC50) constants a nd C(t) is a pharmacokinetic function. Thus an operative model is dR/dt = k(in) . [1 +/- H(C(t))]-k(in) . [1 +/- H(C(t-T-R))] with the baseline condition R-0 = k(in) . T-R. One- and two-compartment cat enary cell models were examined by simulation to describe the role of pharm acokinetics and cell properties. The area under the effect curve (AUCE) was derived. The models were applied to literature data to describe the stimul atory effects of single doses of hematopoietic growth factors such as granu locyte colony-stimulating factor (G-CSF) on neutrophils, thrombopoietin (TP O) on platelets, and erythropoietin (EPO) on reticulocytes in blood. The mo dels described experimental data adequately and provided cell life-spans an d SC50 values. The proposed cell production/loss models can be readily used to analyze the pharmacodynamics of agents which alter cell production yiel ding realistic physiological parameters.