Professor

James E. Polli Ph. D

University of Maryland

School of Pharmacy

20 N Pine, Baltimore, MD 21201, USA. jpolli@rx.umaryland.edu

Dr. James Polli is Associate Professor of Pharmaceutical Sciences at the University of Maryland School of Pharmacy. He received a B.S. in Pharmacy from the Philadelphia College of Pharmacy and Science and a Ph.D. (pharmaceutics) from the University of Michigan. Dr. Polli’s research interest evolves around oral biopharmaceutics and oral drug product performance. His two main research themes deal with the inclusion of bioavailability considerations in drug design and the pharmacokinetic evaluation of oral solid dosage forms. He has published in the areas of dissolution, drug permeability, oral bioavailability, in vitro dissolution - in vivo absorption relationships, and bioequivalence. He currently advises three graduate students. He is Chair of the PQRI BCS Working Group and is a PharmSci and Pharmaceutical Technology Editorial Board member. He served as an advisor to the FDA Immediate Release Dissolution Working Group and an officer in the AAPS PDD section. Dr. Polli has received the AAPS New Investigator Award in Pharmaceutics and Pharmaceutical Technology (1998) and Walter F. Enz-Upjohn Award (1993). He is a licensed pharmacist and teaches professional pharmacy students.

Abstract

One major goal of "in vitro-in vivo correlation" (IVIVC) analysis should be the elucidation of the biopharmaceutic factors that contribute to overall absorption kinetics, including the kinetic role of dissolution. However, it appears that several IVIVC methods do not easily accomplish this goal, particularly for immediate release (IR) products. For example, the USP Level A method typically results in "failing" results for IR products [1]. The USP Level A method for IVIVC is a deconvolution-based approach, where the fraction drug absorbed (Fa) is plotted against the fraction drug dissolved (Fd). The objective of this presentation is to apply an alternative deconvolution-based IVIVC method, denoted the Level AA method, to IR formulations containing drugs from Class I, II, and III. The elucidated biopharmaceutic properties of the dosage forms will be emphasized, including the linkage of IVIVC inferences to Caco-2 permeability.

The following Level AA model was applied to fast and slow dissolving formulations of metoprolol tartrate (Class I), piroxicam (Class II), and randitidine HCl (Class III):

eq 1

where Fa is the fraction of the total amount of drug absorbed at time t, fa is the fraction of the dose absorbed at , is the ratio of the apparent first-order permeation rate constant () to the first-order dissolution rate constant (), and Fd is the fraction of drug dose dissolved at time [2]. The Level A method is a special (linear) case of eq 1. If fa = 1.0 (i.e. complete absorption) and (i.e. strongly dissolution rate-limited absorption), then Fa = Fd.

The Fa vs Fd trajectories for ranitidine and, to a lesser extent, metoprolol formulations exhibited a "reverse L" profile, indicating drug intestinal permeation was rate limiting [3-7]. Meanwhile, the Fa vs Fd trajectories for piroxicam formulations ranged from "reverse L" to "straight line" in shape, indicating intestinal permeation-controlled absorption for fast formulation, yet dissolution-controlled absorption for slow formulation. These results were consistent with the drug substances' biopharmaceutics, including Caco-2 permeability values, and provide a biopharmaceutic understanding of the performance of these IR dosage forms.