Predicting human drug pharmacokinetics from in vitro permeability using an absorption-disposition model.
The purpose of this research is to simulate the in vivo performance of drugs with a wide range of solubility and permeability characteristics formulated as oral dosage forms. The absorption-disposition model was developed using a number of physiological parameters as well as in vitro permeability data generated with Caco-2 cells, 2/4/A1 cells, and hexadecane membranes. A total of 13 drugs with varying solubility and permeability properties were examined using the absorption-disposition model to predict their pharmacokinetic profile. The correlation of predicted and experimentally determined AUC and Cmax, as measures of the pharmacokinetic profile, were >0.96 for all permeation techniques examined. The predictive ability of the model is influenced by the type of permeation method employed; 2/4/A1 cell data yielded the highest degree of accuracy in predicting Cmax and AUC values. The absorption-disposition model developed in this work accurately predicts the in vivo performance of a wide range of orally administered drugs with 8 of 9 drugs examined falling within 80-125% of the experimental value of AUC when using 2/4/A1 cells.
Fliszar
Kyle A
KA
Merck and Co., Inc. Merck Manufacturing Division, West Point, Pennsylvania 19486, USA. Kyle_Fliszar@Merck.com
Hill
Brian T
BT
Foster
Natalie
N
D000284:Administration, Oral; D019540:Area Under Curve; D018938:Caco-2 Cells; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000502:physiology*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000502:physiology*; D007700:Kinetics; D008567:Membranes, Artificial; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D011237:Predictive Value of Tests; D012995:Solubility
D008567:Membranes, Artificial; D004364:Pharmaceutical Preparations