Alison Margolskee (1), Adam S. Darwich (1), Aleksandra Galetin (1), Amin Rostami-Hodjegan (1,2), and Leon Aarons (1)
(1) University of Manchester, Manchester, UK, (2) Simcyp Ltd., Sheffield, UK
Objectives: It is generally believed that IVIVC should be possible for high permeability, dissolution rate limited formulations [1]. The aim of this research was to determine the impact of different rate limiting conditions on the applicability of traditional deconvolution methods to IVIVC.
Methods: Plasma concentration profiles following IV, oral solution, and IR formulation administration were simulated using a simplified absorption and transit model. Intestinal transit, dissolution, and absorption rate constants were varied across a range of values approximately covering those observed in the literature [2,3]. Two traditional deconvolution methods, Wagner-Nelson and numerical deconvolution, were applied to the simulated profiles. IVIVC plots and their corresponding correlation coefficients were analyzed for each combination of parameters to determine the applicability of the deconvolution methods to IVIVC under a range of rate-limiting conditions.
Results: For highly absorbed formulations, the correlation coefficients obtained during IVIVC were comparable for both methods, and steadily declined with decreasing dissolution rate and increasing transit rate. The applicability of numerical deconvolution to IVIVC was not greatly affected by absorption rate, whereas the applicability of Wagner-Nelson fell when dissolution rate overcame absorption rate and absorption became the rate limiting step.
Conclusions: The discrepancy between the expected and deconvolved input arises from the violation of a key assumption of deconvolution, that the unknown input and unit impulse enter the system in the same location. Traditional methods of deconvolution may need to be replaced by more physiologically meaningful models to expand the application of IVIVC to low solubility/permeability compounds and nontraditional formulations.
References:
[1] Dressman, J.B., and C. Reppas. In vitro-in vivo correlations for lipophilic, poorly water-soluble drugs. Eur J Pharm Sci 2000, 11(Suppl 2):S73-80
[2] Yu, L.X., J.R. Crison, and G.L. Amidon. Compartmental transit and dispersion model analysis of small intestinal transit flow in humans. Int J Pharm 1996, 140(1):111-118.
[3] Lennernas H. Human in vivo regional intestinal permeability: importance for pharmaceutical drug development. Mol Pharm 2014, 11(1):12-23.
Reference: PAGE 24 () Abstr 3427 [www.page-meeting.org/?abstract=3427]
Poster: Drug/Disease modeling - Absorption & PBPK