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Development of in vitro-in vivo correlation for extended-release niacin after administration of hypromellose-based matrix formulations to healthy volunteers.
J Pharm Sci. 2014 Nov; 103(11):3713-3723.JP

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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Kesisoglou F
Biopharmaceutics, Pharmaceutical Sciences and Clinical Supply, Merck and Company, Inc., West Point, Pennsylvania 19486. Electronic address: filippos_kesisoglou@merck.com.
Rossenu S
Pharmacokinetics, Pharmacodynamics and Drug Metabolism (PPDM), Merck Sharp and Dohme Ltd., Oss, The Netherlands.
Farrell C
ICON Development Solutions, Marlow, Buckinghamshire, United Kingdom.
Van Den Heuvel M
Pharmacokinetics, Pharmacodynamics and Drug Metabolism (PPDM), Merck Sharp and Dohme Ltd., Oss, The Netherlands.
Prohn M
Pharmacokinetics, Pharmacodynamics and Drug Metabolism (PPDM), Merck Sharp and Dohme Ltd., Oss, The Netherlands.
Fitzpatrick S
Formulation Sciences, Pharmaceutical Sciences and Clinical Supply, Merck Sharp and Dohme Ltd., Hoddesdon, Hertfordshire, United Kingdom.
De Kam PJ
Discovery Medicine, MSD International GmbH, Singapore.
Vargo R
Pharmacokinetics, Pharmacodynamics and Drug Metabolism (PPDM), Merck and Company, Inc., West Point, Pennsylvania 19486.

MeSH

Administration, OralAdolescentAdultBiotransformationChemistry, PharmaceuticalCross-Over StudiesDelayed-Action PreparationsDrug CarriersExcipientsHealthy VolunteersHumansHypromellose DerivativesMiddle AgedModels, BiologicalNiacinNicotinic AcidsRenal EliminationReproducibility of ResultsSolubilityTechnology, PharmaceuticalYoung Adult

Pub Type(s)

Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

25256703

Citation

Kesisoglou, Filippos, et al. "Development of in Vitro-in Vivo Correlation for Extended-release Niacin After Administration of Hypromellose-based Matrix Formulations to Healthy Volunteers." Journal of Pharmaceutical Sciences, vol. 103, no. 11, 2014, pp. 3713-3723.
Kesisoglou F, Rossenu S, Farrell C, et al. Development of in vitro-in vivo correlation for extended-release niacin after administration of hypromellose-based matrix formulations to healthy volunteers. J Pharm Sci. 2014;103(11):3713-3723.
Kesisoglou, F., Rossenu, S., Farrell, C., Van Den Heuvel, M., Prohn, M., Fitzpatrick, S., De Kam, P. J., & Vargo, R. (2014). Development of in vitro-in vivo correlation for extended-release niacin after administration of hypromellose-based matrix formulations to healthy volunteers. Journal of Pharmaceutical Sciences, 103(11), 3713-3723. https://doi.org/10.1002/jps.24179
Kesisoglou F, et al. Development of in Vitro-in Vivo Correlation for Extended-release Niacin After Administration of Hypromellose-based Matrix Formulations to Healthy Volunteers. J Pharm Sci. 2014;103(11):3713-3723. PubMed PMID: 25256703.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Development of in vitro-in vivo correlation for extended-release niacin after administration of hypromellose-based matrix formulations to healthy volunteers. AU - Kesisoglou,Filippos, AU - Rossenu,Stefaan, AU - Farrell,Colm, AU - Van Den Heuvel,Michiel, AU - Prohn,Marita, AU - Fitzpatrick,Shaun, AU - De Kam,Pieter-Jan, AU - Vargo,Ryan, Y1 - 2014/09/24/ PY - 2014/06/17/received PY - 2014/07/24/revised PY - 2014/08/18/accepted PY - 2014/9/27/entrez PY - 2014/9/27/pubmed PY - 2015/6/27/medline KW - controlled release KW - dissolution KW - in vitro/in vivo correlations (IVIVC) KW - mathematical model KW - pharmacokinetics SP - 3713 EP - 3723 JF - Journal of pharmaceutical sciences JO - J Pharm Sci VL - 103 IS - 11 N2 - 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. SN - 1520-6017 UR - https://www.unboundmedicine.com/medline/citation/25256703/Development_of_in_vitro_in_vivo_correlation_for_extended_release_niacin_after_administration_of_hypromellose_based_matrix_formulations_to_healthy_volunteers_ DB - PRIME DP - Unbound Medicine ER -