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

Abstract

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.

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