Gastrointestinal Motility Variation and Implications for Plasma Level Variation: Oral Drug Products

• Published in: Molecular pharmaceutics Vol. 13; no. 2; pp. 557 - 567
• Main Authors: Talattof, Arjang, Price, Judy C, Amidon, Gordon L
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.02.2016
• Subjects: Administration, Oral; Anticholesteremic Agents - administration & dosage; Anticholesteremic Agents - blood; Anticholesteremic Agents - pharmacokinetics; Computer Simulation; Diethylcarbamazine - administration & dosage; Diethylcarbamazine - blood; Diethylcarbamazine - pharmacokinetics; Fatty Acids, Monounsaturated - administration & dosage; Fatty Acids, Monounsaturated - blood; Fatty Acids, Monounsaturated - pharmacokinetics; Fluorouracil - administration & dosage; Fluorouracil - blood; Fluorouracil - pharmacokinetics; Gastric Emptying - drug effects; Gastrointestinal Motility - drug effects; Gastrointestinal Transit - drug effects; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - blood; Immunosuppressive Agents - pharmacokinetics; Indoles - administration & dosage; Indoles - blood; Indoles - pharmacokinetics; Intestinal Absorption - drug effects; Lipoxygenase Inhibitors - administration & dosage; Lipoxygenase Inhibitors - blood; Lipoxygenase Inhibitors - pharmacokinetics; Male; Models, Biological; Tissue Distribution; oral dosage; motility; migrating motor complex; mechanistic physiological model; gastric emptying; bioequivalence; clinical trial simulation
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.5b00774

The oral route of administration is still by far the most ubiquitous method of drug delivery. Development in this area still faces many challenges due to the complexity and inhomogeneity of the gastrointestinal environment. In particular, dosing unpredictably relative to motility phase means the gastrointestinal environment is a random variable within a defined range. Here, we present a mass balance analysis that captures this variation and highlights the effects of gastrointestinal motility, exploring what impacts it ultimately has on plasma levels and the relationship to bioequivalence for high solubility products with both high and low permeability (BCS I and III). Motility-dependent compartmental absorption and transit (MDCAT) mechanistic analysis is developed to describe the underlying fasted state cyclical motility and how the contents of the gastrointestinal tract are propelled.