A biowaiver monograph of pyrazinamide based on literature data together with some additional experimental data is presented. The risks of basing a bioequivalence (BE) assessment on in vitro rather than in vivo study results for the approval of new immediate release (IR) solid oral dosage forms containing pyrazinamide (‘‘biowaiving’’), including both reformulated products and new multisource drug products, are evaluated under consideration of its biopharmaceutical and clinical properties. This evaluation refers to drug products containing pyrazinamide as the only active pharmaceutical ingredient (API) and not to combination products.
The purpose and scope of this series of monographs have been previously discussed. Summarized in few words, the aim is to evaluate all pertinent data available from literature sources for a given API to assess the risks associated with a biowaiver. For these purposes, risk is deﬁned as the probability of an incorrect biowaiver decision as well as the consequences of the decision in terms of public health and individual patient risks. On the basis of these considerations, a recommendation can be made as to whether a biowaiver approval is advisable or not. This systematic approach to recommend or advise against a biowaiver decisions is referred to in the recently published World Health Organization (WHO) Guideline. It is pointed out that these monographs do not simply apply this WHO Guideline, nor the FDA and/or EMEA Guidance, but also want to serve as a critical validation of these regulatory documents. Biowaiver monographs have already been published for acetaminophen (INN: paracetamol), amitriptyline, atenolol, chloroquine, cimetidine, ethambutol, ibuprofen, isoniazid, prednisolone, prednisone, propranolol, ranitidine, and verapamil. They are also available online at the website of the International Pharmaceutical Federation FIP.
Pyrazinamide is one of the key APIs used in the combination treatment of tuberculosis recommended by the WHO. The standard regime currently calls for initial therapy with isoniazid,
rifampicin, pyrazinamide, and ethambutol for the ﬁrst 2 months, followed by a continuation phase comprising isoniazid and rifampicin which lasts 4 months. Pyrazinamide is used in the initial phase of the treatment for its bactericidal activity against slowly metabolizing bacilli, which results in a low incidence of bacteriological relapse after completion of the chemotherapy regimen. The mechanism of action of pyrazinamide is not fully elucidated. The antimicrobial activity of this synthetic analogue of nicotinamide appears to depend partly on a conversion to its primary metabolite, pyrazinoic acid, in an acidic environment. The metabolite interacts with mycobacterial pyrazinamidase present in in vitro susceptible strains of Mycobacterium tuberculosis.
Pyrazinamide occurs in four polymorphic forms with different crystal structures: α-, β-, γ-, and r-pyrazinamide, depending on the solvent and the temperature used in the manufacturing process.
Differences in solubility of the four polymorphic forms have not been reported. The pharmacopoeias do not stipulate any speciﬁc polymorph.
Pyrazinamide is an extremely weak base. A pKa value of 0.5 (no temperature speciﬁed) has been reported in the literature.
Dosage Form Strengths
The WHO Essential Medicines List speciﬁes a 400 mg tablet dosage form of pyrazinamide.
Single API dosage forms with an MA in Germany (DE), Denmark (DK), Finland (FI), France
(FR), The Netherlands (NL), and the USA (USA) contain 500 mg pyrazinamide.
Permeability and Absorption
No studies investigating the in situ or ex vivo intestinal permeability, absolute bioavailability
(BA) or Caco-2 cell studies could be identiﬁed in the literature. It is widely believed that pyrazinamide is nearly fully absorbed from the gut. In a study carried out by Ellard as early as 1969, a urinary recovery of about 40% after 48 h was measured after administration of an oral dose of 1500 and 3000 mg to healthy subjects. In another leg of this study, referred to as the Nairobi ‘‘crossover study,’’ 34–35% of an oral dose of 500 mg administered three times a day, 1500 mg once a day or 3000 mg once a day were recovered in the urine of patients with tuberculosis after 24 h. In the same study, using extraction with subsequent coupling color reaction and measurement of the optical density as the analytical method, no API could be detected in the aqueous acetone extracts of feces. Lacroix et al. found a cumulative urinary excretion of 73% of the ingested oral dose of pyrazinamide and its metabolites 72 h after administration of a single oral dose of 27 mg/kg to healthy subjects. On the basis of this information the authors hypothesized that pyrazinamide possesses a high BA. In children, the absorption of pyrazinamide appears to be delayed and sometimes reduced.
C. BECKER, JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008