The plateau principle is a mathematical model or scientific law originally developed to explain the time course of drug action (pharmacokinetics). The principle has wide applicability in pharmacology, physiology, nutrition, biochemistry, and system dynamics. It applies whenever a drug or nutrient is infused or ingested at a relatively constant rate and when a constant fraction is eliminated during each time interval. Under these conditions, any change in the rate of infusion leads to an exponential increase or decrease until a new level is achieved. This behavior is also called an approach to steady state because rather than causing an indefinite increase or decrease, a natural balance is achieved when the rate of infusion or production is balanced by the rate of loss. An especially important use of the plateau principle is to study the renewal of tissue constituents in the human and animal body. In adults, daily synthesis of tissue constituents is nearly constant, and most constituents are removed with a first-order reaction rate. Applicability of the plateau principle was recognized during radioactive tracer studies of protein turnover in the 1940s by Rudolph Schoenheimer and David Rittenberg. Unlike the case with drugs, the initial amount of tissue or tissue protein is not zero because daily synthesis offsets daily elimination. In this case, the model is also said to approach a steady state with exponential or logarithmic kinetics. Constituents that change in this manner are said to have a biological half-life. A practical application of the plateau principle is that most people have experienced "plateauing" during regimens for weight management or training for sports. After a few weeks of progress, one seems unable to continue gaining in ability or losing weight. This outcome results from the same underlying quantitative model. This entry will describe the popular concepts as well as development of the plateau principle as a scientific, mathematical model. In the sciences, the broadest application of the plateau principle is creating realistic time signatures for change in kinetic models (see Mathematical model). One example of this principle is the long time required to effectively change human body composition. Theoretical studies have shown that many months of consistent physical training and food restriction are needed to bring about permanent weight stability in people who were previously overweight.
The plateau principle in pharmacokinetics Most drugs are eliminated from the blood plasma with first-order kinetics. For this reason, when a drug is introduced into the body at a constant rate by intravenous therapy, it approaches a new steady concentration in the blood at a rate defined by its half-life. Similarly, when the intravenous infusion is ended, the drug concentration decreases exponentially and reaches an undetectable level after 5–6 half-lives have passed. If the same drug is administered as a bolus (medicine) with a single injection, peak concentration is achieved almost immediately and then the concentration declines exponentially. Most drugs are taken by mouth. In this case, the assumption of constant infusion is only approximated as doses are repeated over the course of several days. The plateau principle still applies but more complex models are required to account for the route of administration.
Equations for the approach to steady state Derivation of equations that describe the time course of change for a system with zero-order input and first-order elimination are presented in the articles Exponential decay and Biological half-life, and in scientific literature.
C t = C 0 e − k e t {\displaystyle C_{t}=C_{0}e^{-k_{e}t}\,}
Ct is concentration after time t C0 is the initial concentration (t = 0) ke is the elimination rate constant The relationship between the elimination rate constant and half-life is given by the following equation:
k e = ln 2 t 1 / 2 {\displaystyle k_{e}={\frac {\ln 2}{t_{1/2}}}\,}
Because ln 2 equals 0.693, the half-life is readily calculated from the elimination rate constant. Half-life has units of time, and the elimination rate constant has units of 1/time, e.g., per hour or per day. An equation can be used to forecast the concentration of a compound at any future time when the fractional degration rate and steady state concentration are known:
C t = C 0 + ( C s s − C 0 ) ( 1 − e − k e t ) {\displaystyle C_{t}=C_{0}+(C_{ss}-C_{0})(1-e^{-k_{e}t})\,}
Css is concentration after the steady state has been achieved. The exponential function in parentheses corresponds to the fraction of total change that has been achieved as time passes and the difference between Css and C0 equals the total amount of change. Finally, at steady state, the concentration is expected to equal the rate of synthesis, production or infusion divided by the first-order elimination constant.
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