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Indirect pharmacodynamic models for responses with circadian removal.

ABSTRACT: Rhythmicity in baseline responses over a 24-h period for an indirect pharmacological effect R(t) can arise from either a periodic time-dependent input rate [Formula: see text] or a periodic time-dependent loss constant [Formula: see text]. If either [Formula: see text] or [Formula: see text] follows some nonstationary biological rhythm (e.g., circadian), then the response R(t) also displays a periodic behavior. Indirect response models assuming time-dependent input rates [Formula: see text] have been utilized to capture drug effects on various physiological responses such as hormone suppression, immune cell trafficking, and gene expression in tissues. This paradigm was extended to consider responses with circadian-controlled loss [Formula: see text] mechanisms. Theoretical equations describing this model are presented and simulations were performed to examine expected response behaviors. The model was able to capture the chronobiology and pharmacodynamics of applicable drug responses, including the uricosuric effects of lesinurad in humans, suppression of the beta amyloid (A?) peptide by a gamma-secretase inhibitor in mouse brain, and the modulation of extracellular dopamine by a dopamine transporter inhibitor in rat brain. This type of model has a mechanistic basis and shows utility for capturing drug responses displaying nonstationary baselines controlled by removal mechanism(s).

SUBMITTER: Ayyar VS

PROVIDER: S-EPMC6447046 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Indirect pharmacodynamic models for responses with circadian removal.

Ayyar Vivaswath S VS Krzyzanski Wojciech W Jusko William J WJ

Journal of pharmacokinetics and pharmacodynamics 20190129 1

Rhythmicity in baseline responses over a 24-h period for an indirect pharmacological effect R(t) can arise from either a periodic time-dependent input rate [Formula: see text] or a periodic time-dependent loss constant [Formula: see text]. If either [Formula: see text] or [Formula: see text] follows some nonstationary biological rhythm (e.g., circadian), then the response R(t) also displays a periodic behavior. Indirect response models assuming time-dependent input rates [Formula: see text] have ...[more]

PMID: 30694437

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Project description:Transit compartments (TC) models are used to describe pharmacodynamic responses that involve drug action on cells undergoing differentiation and maturation. Such pharmacodynamic systems can also be described by lifespan based indirect response (LIDR) models. The purpose of this report is to investigate conditions under which the transit compartments models can be considered a special case of LIDR models. An integral representation of a solution to TC model has been used to determine the lifespan distribution for cell population described by this model. The distribution served as a basis for definition of new LIDRE (lifespan based indirect response with an effect on the lifespan distribution) models. Time courses of responses described by both types of models were simulated for a monoexponential pharmacokinetic function. The limit response was calculated as the number of transit compartments approached infinity. The difference between the limit response and TC responses were evaluated by computer simulations using MATLAB 7.7. TC models are a special case of LIDR models with the lifespan distribution described by the gamma function. If drug affects only the production of cells, then the cell lifespan distribution is time invariant. In this case an increase in the number of compartments results in a basic LIDR model with a point lifespan distribution. When the drug inhibits or stimulates cell aging, the cell lifespan distribution becomes time dependent revealing a new mechanism for drug effect on the gamma probability density function. The TC model with a large number of transit compartments converges to an LIDRE model. The limit LIDR models are approximated by the TC models when the number of compartments is at least 5. A moderate improvement in the approximation is observed if this number exceeds 20. The lifespan distribution for a cell population described by a TC model is described by the gamma probability density function. A drug affects this distribution only if it stimulates or inhibits the rate of cell maturation. If the number of transit compartments increases, then the TC model converges to a new type of LIDR model.

Dataset Information

Indirect pharmacodynamic models for responses with circadian removal.

Publications

Indirect pharmacodynamic models for responses with circadian removal.

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