Retrospective and Prospective Human Intravenous and Oral Pharmacokinetic Projection of Dipeptidyl peptidase-IV Inhibitors Using Simple Allometric Principles – Case Studies of ABT-279, ABT-341, Alogliptin, Carmegliptin, Sitagliptin and Vildagliptin

摘要

Purpose: The purpose of this exercise was to explore the utility of allometric scaling approach for the prediction of intravenous and oral pharmacokinetics of six dipeptidy peptidase-IV (DPP-IV) inhibitors viz. ABT-279, ABT-341, alogliptin, carmegliptin, sitagliptin and vildagliptin. Methods: The availability of intravenous and oral pharmacokinetic data in animals enabled the allometry scaling of 6 DPP-IV inhibitors. The relationship between the main pharmacokinetic parameters [viz. volume of distribution (V d ) and clearance (CL)] and body weight was studied across three or four mammalian species, using double logarithmic plots to predict the human pharmacokinetic parameters of CL and V d using simple allometry. Results: A simply allometry relationship: Y = aW b was found to be adequate for the prediction of intravenous and oral human clearance/volume of distribution for DPP-IV inhibitors. The allometric equations for alogliptin, carmegliptin, sitagliptin, vildagliptin, ABT-279 and ABT-341 were 1.867W 0.780 , 1.170W 0.756 , 2.020W 0.529 , 1.959 W 0.847 , 0.672 W 1.016 , 1.077W 0.649 , respectively, to predict intravenous clearance (CL) and the corresponding equations to predict intravenous volume of distribution (V d ) were: 3.313W 0.987 , 6.096W 0.992 , 7.140W 0.805 , 2.742W 0.941 , 1.299W 0.695 and 5.370W 0.803 . With the exception of a few discordant values the exponent rule appeared to hold for CL (0.75) and V d (1.0) for the predictions of various DPP-IV inhibitors. Regardless of the routes, the predicted values were within 2-3 fold of observed values and intravenous allometry was better than oral allometry. Conclusion: Simple allometry retrospectively predicted with reasonable accuracy the human reported values of gliptins and could be used as a prospective tool for this class of drugs. This article is open to POST-PUBLICATION REVIEW . Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.