Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Isoniazid**A project of the International Pharmaceutical Federation FIP, Groupe BCS, www.fip.org/bcs.

Abstract

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing isoniazid as the only active pharmaceutical ingredient (API) are reviewed. Isoniazid's solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. Isoniazid is "highly soluble" but data on its oral absorption and permeability are inconclusive, suggesting this API to be on the borderline of BCS Class I and III. For a number of excipients, an interaction with the permeability is extreme unlikely, but lactose and other deoxidizing saccharides can form condensation products with isoniazid, which may be less permeable than the free API. A biowaiver is recommended for IR solid oral drug products containing isoniazid as the sole API, provided that the test product meets the WHO requirements for "very rapidly dissolving" and contains only the excipients commonly used in isoniazid products, as listed in this article. Lactose and/or other deoxidizing saccharides containing formulations should be subjected to an in vivo BE study.

The Effect of Excipients on the Permeability of BCS Class III Compounds and Implications for Biowaivers

“…Biowaivers for Class III compounds should be considered when excipients used in a formulation have been shown not to affect permeability. There are many recent examples of biowaivers granted by the WHO for Class III drugs ( 34 – 38 ), as well as the assessment that BE of many of the IR drug products available today can be assured with an in vitro dissolution test ( 39 ). The results of this study support biowaivers for BCS Class III compounds.…”

PharmGKB summary

“…Absorption may be reduced by concomitant administration of sugar or following food intake. This is likely due to the conversion of INH to a hydrazone species, making it less available for absorption [21–23]. INH seems to be widely distributed to all fluids and tissues, according to the apparent value of distribution volume (0.6 L/kg on average), with the largest accumulation in the liver; the pharmacological model for INH seems to follow first-order kinetics [24].…”

“…Hz can be broken down to ammonia or acetylated to AcHz by NAT2 [27–29]. None of the metabolites have known antitubercular properties, apart from the hepatotoxic AcHz [23]. …”

An Enzyme-Induced Novel Biosensor for the Sensitive Electrochemical Determination of Isoniazid

“…However, regular overdoses of INZ cause hepatotoxicity and may lead to death [2]. The World Health Organization (WHO) suggested that a daily dose of INZ per adult should be 4–6 mg/kg of their body weight [3]. INZ possesses both bacteriostatic and bactericidal action to interfere with the metabolism of nucleic acids, bacterial proteins, carbohydrates, and lipids.…”