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J Pharm Sci. 2016 Apr;105(4):1362-9. doi: 10.1016/j.xphs.2016.01.017. Epub 2016 Mar 5.

Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Ribavirin.

Author information

1
Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
2
Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
3
Pharmaceutical Development, AstraZeneca R&D, Mölndal, Sweden.
4
Brazilian Health Surveillance Agency (Anvisa), Division of Therapeutic Equivalence, Brasilia, Brazil.
5
RIVM - National Institute for Public Health and the Environment, Bilthoven, Utrecht, The Netherlands.
6
Institute of Pharmacy, Johannes Gutenberg University, Mainz, Germany.
7
Food and Drug Administration, Center for Drug Evaluation, Silver Spring, Maryland 20993.
8
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201.
9
International Pharmaceutical Federation FIP, The Hague, The Netherlands.
10
Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany. Electronic address: dressman@em.uni-frankfurt.de.

Abstract

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release solid oral dosage forms containing ribavirin are reviewed. Ribavirin is highly soluble, but its permeability characteristics are not well defined. Therefore according to the Biopharmaceutical Classification System, and taking a "worst case" approach, ribavirin should be assigned to class III. As ribavirin is transported across the brush border membrane of the human jejunum by hCNT2, it shows saturable uptake in the intestine. However, no common excipients have been shown to compete for ribavirin absorption, nor have problems with BE of immediate release ribavirin formulations containing different excipients and produced by different manufacturing methods been reported in the open literature. So the risk of bioinequivalence caused by these factors appears to be low. Ribavirin is considered a narrow therapeutic index drug, as judged by comparing the minimum effective concentration and minimum toxic concentrations in blood. Although ribavirin would not be eligible for approval via a Biopharmaceutical Classification System-based biowaiver procedure according to today's guidances due to its narrow therapeutic index, the risks of biowaiving should be weighed against the considerable risks associated with studying BE of ribavirin products in healthy subjects.

KEYWORDS:

BCS; absorption; biowaiver; permeability; ribavirin; solubility

PMID:
26952879
DOI:
10.1016/j.xphs.2016.01.017
[Indexed for MEDLINE]

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