title: Development of in vitro-in vivo correlation for extended-release niacin after administration of hypromellose-based matrix formulations to healthy volunteers.
abstract: Development of in vitro-in vivo correlations (IVIVCs) for extended-release (ER) products is commonly pursued during pharmaceutical development to increase product understanding, set release specifications, and support biowaivers. This manuscript details the development of Level C and Level A IVIVCs for ER formulations of niacin, a highly variable and extensively metabolized compound. Three ER formulations were screened in a cross-over study against immediate-release niacin. A Multiple Level C IVIVC was established for both niacin and its primary metabolite nicotinuric acid (NUA) as well as total niacin metabolites urinary excretion. For NUA, but not for niacin, Level A IVIVC models with acceptable prediction errors were achievable via a modified IVIVC rather than a traditional deconvolution/convolution approach. Hence, this is in contradiction with current regulatory guidelines that suggest that when a Multiple Level C IVIVC is established, Level A models should also be readily achievable. We demonstrate that for a highly variable, highly metabolized compound such as niacin, development of a Level A IVIVC model fully validated according to agency guidelines may be challenging. However, Multiple Level C models are achievable and could be used to guide release specifications and formulation/manufacturing changes.
authors.affiliation: Biopharmaceutics, Pharmaceutical Sciences and Clinical Supply, Merck and Company, Inc., West Point, Pennsylvania 19486. Electronic address: filippos_kesisoglou@merck.com.
authors.forename: Filippos
authors.initials: F
authors.lastname: Kesisoglou
authors.affiliation: Pharmacokinetics, Pharmacodynamics and Drug Metabolism (PPDM), Merck Sharp and Dohme Ltd., Oss, The Netherlands.
authors.forename: Stefaan
authors.initials: S
authors.lastname: Rossenu
authors.affiliation: ICON Development Solutions, Marlow, Buckinghamshire, United Kingdom.
authors.forename: Colm
authors.initials: C
authors.lastname: Farrell
authors.affiliation: Pharmacokinetics, Pharmacodynamics and Drug Metabolism (PPDM), Merck Sharp and Dohme Ltd., Oss, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: Van Den Heuvel
authors.affiliation: Pharmacokinetics, Pharmacodynamics and Drug Metabolism (PPDM), Merck Sharp and Dohme Ltd., Oss, The Netherlands.
authors.forename: Marita
authors.initials: M
authors.lastname: Prohn
authors.affiliation: Formulation Sciences, Pharmaceutical Sciences and Clinical Supply, Merck Sharp and Dohme Ltd., Hoddesdon, Hertfordshire, United Kingdom.
authors.forename: Shaun
authors.initials: S
authors.lastname: Fitzpatrick
authors.affiliation: Discovery Medicine, MSD International GmbH, Singapore.
authors.forename: Pieter-Jan
authors.initials: PJ
authors.lastname: De Kam
authors.affiliation: Pharmacokinetics, Pharmacodynamics and Drug Metabolism (PPDM), Merck and Company, Inc., West Point, Pennsylvania 19486.
authors.forename: Ryan
authors.initials: R
authors.lastname: Vargo
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001711:Biotransformation; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005079:Excipients / Q000737:chemistry; D064368:Healthy Volunteers; D006801:Humans; D065347:Hypromellose Derivatives / Q000737:chemistry*; D008875:Middle Aged; D008954:Models, Biological; D009525:Niacin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D009539:Nicotinic Acids / Q000493:pharmacokinetics; D065667:Renal Elimination; D015203:Reproducibility of Results; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D055815:Young Adult
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005079:Excipients; D009539:Nicotinic Acids; D009525:Niacin; D065347:Hypromellose Derivatives; C002477:nicotinuric acid
keywords: controlled release; dissolution; in vitro/in vivo correlations (IVIVC); mathematical model; pharmacokinetics