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Abstract
In vitro-in vivo correlations (IVIVCs) play an important role in formulation development and drug approval. At the heart of IVIVC is deconvolution, the method of deriving an in vivo “dissolution profile” for comparison with in vitro dissolution data. IVIVCs are generally believed to be possible for highly permeable and highly soluble compounds with release/dissolution as the rate-limiting step. In this manuscript, we apply the traditional deconvolution methods, Wagner-Nelson and numerical deconvolution, to profiles simulated using a simplified small intestine absorption and transit model. Small intestinal transit, dissolution, and absorption rate constants are varied across a range of values approximately covering those observed in the literature. IVIVC plots and their corresponding correlation coefficients are analyzed for each combination of parameters to determine the applicability of the deconvolution methods under a range of rate-limiting conditions. For highly absorbed formulations, the correlation coefficients obtained during IVIVC are comparable for both methods and steadily decline with decreasing dissolution rate and increasing transit rate. The applicability of numerical deconvolution to IVIVC is not greatly affected by absorption rate, whereas the applicability of Wagner-Nelson falls when dissolution rate overcomes absorption rate and absorption becomes the rate-limiting step. 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.
Highlights
In vitro-in vivo correlations (IVIVC) play an important role in the production and approval of drug products and formulations
We focus on the traditional deconvolution methods, Wagner-Nelson and numerical deconvolution, and their applicability under different rate-limiting conditions
Plotting this simulated in vitro dissolution profile against the dissolution/absorption profile deconvolved from the simulated in vivo profiles, one can determine whether an IVIVC can be established
Summary
In vitro-in vivo correlations (IVIVC) play an important role in the production and approval of drug products and formulations. At the heart of IVIVC is deconvolution, the method of deriving an in vivo “dissolution profile” for point by point comparison with in vitro dissolution data in what is termed a “level A” IVIVC by the FDA [2]. The traditional methods, Wagner-Nelson and Loo-Reigelman, appeared in the 1960s [3,4] These methods have been used extensively to determine the absorption kinetics following an oral administration, and Wagner-Nelson is still the most frequently used method in IVIVC. Numerical deconvolution emerged in the 1970s as an alternative method of calculating drug input rates [5] (whether it be the rate of absorption or rate of dissolution)
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