Читать книгу Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations - Sheila Annie Peters - Страница 31

Most drugs are expected to have linear PK at therapeutic concentrations. However, multiple factors can contribute to nonlinearity even at therapeutic concentrations. For drugs in infection and cancer therapeutic areas, where therapeutic doses are generally high, the high drug concentrations can saturate the enzymes and transporters that are involved in their metabolism and elimination in the gut, liver, and other elimination organs. For example, nonlinear PK is frequently observed for antiretroviral drugs. Drugs that inhibit or induce enzymes can cause auto‐inhibition or auto‐induction, leading to time‐ or concentration‐dependent changes in exposure. Drugs binding plasma proteins, especially to AGP can also exhibit nonlinear kinetics due to the saturation of protein binding. Certain drugs (most monoclonal antibody drugs and some small molecules) bind to their pharmacological target (such as a receptor) with high affinity. The internalization of the receptor–drug complex triggered by the high‐affinity receptor binding can then influence the distribution and elimination of the drug. This phenomenon is called target‐mediated drug disposition (TMDD). Saturation of enzyme‐, transporter‐ and plasma proteins, autoinhibition, autoinduction, and TMDD‐driven clearance leads to higher exposures at higher doses, while autoinduction leads to lower exposures at higher doses. Poorly soluble drugs with high therapeutic doses are at a risk of incomplete absorption and therefore lower exposures at higher doses. An important clinical implication of nonlinear pharmacokinetics (Ludden, 1991) is the altered half‐life, which leads to a longer or shorter time to achieve a given fraction of steady state. Since dose predictions are often done for the steady state, nonlinearity makes any predictions of disposition highly uncertain.