Abstract. This article describes regulatory approaches for approval of Bgeneric^orally inhaled drug products (OIDPs) in the United States, European Union, Brazil, China and India. While registration of a generic OIDP in any given market may require some documentation of the formulation and device similarity to the Boriginal^product as well as comparative testing of in vitro characteristics and in vivo performance, the specific documentation approaches, tests and acceptance criteria vary by the country. This divergence is due to several factors, including unique cultural, historical, legal and economic circumstances of each region; the diverse healthcare and regulatory systems; the different definitions of key terms such as Bgeneric^and Breference^drug; the acknowledged absence of in vitro in vivo correlations for OIDPs; and the scientific and statistical issues related to OIDP testing (such as how best to account for the batch-to-batch variability of the Reference product, whether to use average bioequivalence or population bioequivalence in the statistical analysis of results, whether to use healthy volunteers or patients for pharmacokinetic studies, and which pharmacodynamic or clinical end-points should be used). As a result of this discrepancy, there are ample opportunities for the regulatory and scientific communities around the world to collaborate in developing more consistent, better aligned, science-based approaches. Moving in that direction will require both further research and further open discussion of the pros and cons of various approaches.

Both the capecitabine tablet formulations demonstrated equivalent rate and extent of systemic absorption, and hence were considered bioequivalent. Therefore, the two formulations can be considered as equivalent in terms of pharmacokinetics and safety profiles.

Generic fixed-dose combinations of antiretrovirals are frequently prescribed for the treatment of human immunodeficiency virus infection. A randomized, 2-way study was conducted in 24 fasting, healthy, Indian male subjects to assess bioequivalence between a single combination tablet containing lamivudine, stavudine, and nevirapine (treatment A) with respect to separate marketed tablets administered simultaneously (treatment B). Each subject received treatments A and B separated by 19 days of a drug-free washout period. Plasma concentrations of antiretrovirals, determined by a validated liquid chromatography/tandem mass spectrometry assay, were used to assess pharmacokinetic parameters such as maximum observed plasma concentration and area under the plasma concentration curve. Pharmacokinetic parameters were comparable for either treatment. As geometric mean ratios (% treatment A/treatment B) of log-transformed parameters of area under the plasma concentration curve and plasma concentration, as well as their resultant 90% confidence intervals, were within 80% to 125% and 75% to 133%, respectively, 2 treatments were considered bioequivalent in the extent and rate of absorption. Both treatments exhibited similar tolerability under fasting conditions.

Sepsis with subsequent multiple organ failure is the commonest complication seen in the surgical intensive care unit today. A gut mucosal barrier dysfunction is assuming an increasingly important role as one possible explanation for the initiation of the septic process. It is known that the gut bacteria and endotoxins can, in the presence of a seemingly intact epithelium, translocate to extraintestinal sites, but the exact mechanism behind this process is not understood. In the present study we have approached this problem by testing the gut permeability to two macromolecules, bovine serum albumin (BSA) and fluorescein isothiocyanate (FITC)-dextran, after 7 days of enteral or parenteral nutrition in the rat. The plasma values of FITC-dextran after 4 h of marker feeding showed a significant increase in gut permeability after parenteral but not after enteral nutrition as compared with the controls. The plasma values of BSA, however, did not show any significant change in any of the groups. Thus, parenteral nutrition, with the changes occurring in the gut mucosa, may be one of the etiologic co-factors behind a gut mucosal barrier dysfunction, eventually leading to absorption of noxious agents into the systemic circulation with subsequent multiple organ failure.

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