Date Published: December 14, 2015
Publisher: Springer US
Author(s): Alison Margolskee, Adam S. Darwich, Aleksandra Galetin, Amin Rostami-Hodjegan, Leon Aarons.
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.
In vitro-in vivo correlations (IVIVC) play an important role in the production and approval of drug products and formulations. Once an IVIVC is established for a set of formulations, then in vitro dissolution tests can be used in place of further bioequivalence studies in the production or modification of different formulations (1). Thus, IVIVCs play an important role in the industry, saving time, money, and unnecessary clinical trials. 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).
A simplified absorption and transit model was used to test the effects of changing dissolution, absorption, and transit rates on the applicability of two deconvolution methods in establishing IVIVCs. Intestinal transit, dissolution, and absorption rates were varied across physiologically meaningful ranges obtained from the literature. For each combination of parameters, the profiles following administration of an oral solution and an immediate release formulation were simulated. Wagner-Nelson and numerical deconvolution were applied to obtain the deconvolved absorption profiles. These absorption profiles were plotted against the respective fraction dissolved curves representing the in vitro dissolution curves that would be used to establish an IVIVC. The corresponding correlation coefficients for each in vitro fraction dissolved vs. in vivo fraction absorbed plot were calculated in order to gauge the effect of transit, dissolution, and absorption rates on the interpretation of deconvolution. Following the analysis of the applicability of these methods to IVIVC in different situations, we analytically deconvolved absorption models of smaller size to obtain closed form solutions to the deconvolved input so that the reasons for the discrepancies between the deconvolution methods and the simulated in vitro dissolution profile could be determined. The equations associated with Wagner-Nelson and numerical deconvolution used in this investigation are provided in the Appendix.
Wagner-Nelson was applied to the simulated oral formulation concentration profiles, and numerical deconvolution was applied to the oral formulation profile, using the oral solution profile as the unit impulse response (UIR) (see Appendix for more details on the application of these methods). For the elimination rate constant which is needed in the calculation of fraction absorbed (fa) via Wagner-Nelson, we used the actual value of ke from the simulations, in order to avoid the possibility of flip-flop kinetics that can occur when ka or kD is the rate-limiting step. This simulates the ideal scenario in which one had the perfect intravenous bolus UIR. During numerical deconvolution, the deconvolved input for the oral formulation was assumed to take the form of a continuous piecewise quadratic with continuous first derivative (12).
Supposing it was possible to perform the perfect in vitro experiment that would exactly match the in vivo dissolution kinetics, we might assume the widely accepted deconvolution methods would be able to obtain a reasonable IVIVC. Plotting the first order dissolution curve using the simulated in vivo first order rate constant gives us this theoretically perfect in vitro dissolution profile. 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.
The performance of both the Wagner-Nelson and numerical deconvolution methods during IVIVC is comparable for highly absorbed formulations, steadily declining with decreasing dissolution rate and increasing transit rate. The applicability of numerical deconvolution to IVIVC is not greatly affected by absorption rate, whereas the performance of Wagner-Nelson declines when absorption is the rate-limiting step. The theory of deconvolution relies on the underlying assumption that the unknown input and unit impulse enter the system in the same location, which is violated for slow release formulations. In order to broaden the scope of IVIVC, we must bridge the gap between in vitro dissolution and in vivo response, pushing the in vitro and in silico closer to in vivo conditions.