title: Deconvolution and IVIVC: Exploring the Role of Rate-Limiting Conditions.
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.
authors.affiliation: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Manchester, UK. alison.margolskee@manchester.ac.uk.
authors.forename: Alison
authors.initials: A
authors.lastname: Margolskee
authors.affiliation: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Manchester, UK.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Darwich
authors.affiliation: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Manchester, UK.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Galetin
authors.affiliation: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Manchester, UK.|Certara, Sheffield, UK.
authors.forename: Amin
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.affiliation: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Manchester, UK.
authors.forename: Leon
authors.initials: L
authors.lastname: Aarons
mesh_terms: D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical / Q000379:methods* / Q000639:trends; D008962:Models, Theoretical; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility
chemical_list: D004364:Pharmaceutical Preparations
keywords: absorption; dissolution; in vitro-in vivo correlation (IVIVC); numerical deconvolution; pharmacokinetic modeling