Basic pharmacodynamic models for agents that alter the lifespan distribution of natural cells

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Abstract

A new class of basic indirect pharmacodynamic models for agents that alter the loss of natural cells based on a lifespan concept are presented. The lifespan indirect response (LIDR) models assume that cells (R) are produced at a constant rate (kin), survive during a certain duration TR, and finally are lost. The rate of cell loss is equal to the production rate but is delayed by TR. A therapeutic agent can increase or decrease the baseline cell lifespan to a new cell lifespan, TD, by temporally changing the proportion of cells belonging to the two modes of the lifespan distribution. Therefore, the change of lifespan at time t is described according to the Hill function, H(C(t)), with capacity (Emax) and sensitivity (EC50), and the pharmacokinetic function C(t). A one-compartment cell model was examined through simulations to describe the role of pharmacokinetics, pharmacodynamics and cell properties for the cases where the drug increases (TD > TR) or decreases (TD < TR) the cell lifespan. The area under the effect curve (AUCE) and explicit solutions of LIDR models for large doses were derived. The applicability of the model was further illustrated using the effects of recombinant human erythropoietin (rHuEPO) on reticulocytes. The cases of both stimulation of the proliferation of bone marrow progenitor cells and the increase of reticulocyte lifespans were used to describe mean data from healthy subjects who received single subcutaneous doses of rHuEPO ranging from 20 to 160 kIU. rHuEPO is about 4.5-fold less potent in increasing reticulocyte survival than in stimulating the precursor production. A maximum increase of 4.1 days in the mean reticulocyte lifespan was estimated and the effect duration on the lifespan distribution was dose dependent. LIDR models share similar properties with basic indirect response models describing drug stimulation or inhibition of the response loss rate with the exception of the presence of a lag time and a dose independent peak time. The current concept can be applied to describe the pharmacodynamic effects of agents affecting survival of hematopoietic cell populations yielding realistic physiological parameters.

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