Challenges of advanced dosage forms and delivery systems
Advances in pharmaceutical science and technology have led to an increasing growth in pharmaceutical dosage forms, including
the availability of various modified-release platforms (e.g., sustained-, delayed-, and pulsatile-release) and complex drug
delivery systems (e.g., liposomes, drug-eluting stents, and nanotechnology-derived products). In view of the intricate features
of these products, pharmaceutical scientists have encountered significant challenges, ranging from designing and manufacturing
such products with high quality to demonstrating and evaluating therapeutic equivalence between generic and innovator drugs.
The following is a recent example relating to the establishment of bioequivalence of liposome drug products. Liposomes are
microscopic vesicles comprising one or more bilayers of amphipathic lipid molecules that enclose one or more aqueous compartments.
Drug distribution in liposomes depends on the lipophilicity of the incorporated drug. Doxil (doxorubicin HCl liposome injection,
Ortho Biotech Products, Bridgewater, NJ) is an example in which doxorubicin, a hydrophilic drug, is encapsulated in the aqueous
space of the liposomes. In contrast, amphotericin B is hydrophobic, thus it is intercalated within the lipid bilayers of AmBisome
(amphotericin B, Gilead Sciences, Foster City, CA). With the lipophilic surface, AmBisome is easily taken up by the endogenous
macrophages residing in the reticuloendothelial system (RES). As a result, AmBisome has a relatively short residence time
in the blood. On the contrary, the stealth liposome structure of Doxil protects the liposomes from RES uptake and prolongs
circulation time in the bloodstream. With its long residence time in the blood and its small particle size (~100 nm), Doxil
possesses an increased permeability through the altered and often compromised vasculature of tumors.
Given the potential of phagocytosis and extravasation processes occurring in vivo, one of the regulatory questions that have arisen is whether blood-level measurement can be used to assess bioequivalence
of liposome drug products (4, 5). To address this question, one must understand the disposition of the liposome product under
examination. For most conventional liposomes that are prone to RES uptake, it is unlikely that blood levels can be used to
determine bioequivalence. Liposomes that are designed to avoid RES uptake may be able to circulate in the bloodstream for
a long period of time. However, these liposomes have a greater chance of extravasating through the leaky vascular wall into
various tissues. At issue is whether one can demonstrate that the test and reference products have comparable "rate and extent
to which the active ingredient or active moiety becomes available at the site of action," a regulatory mandate for establishing
bioequivalence (2). It is conceivable that similar questions may be raised for other targeted delivery systems, advanced dosage
forms, and combination products.
The trend in the evaluation of therapeutic equivalence
In retrospect, over the decades, the field of biopharmaceutics has evolved from empirical science that investigates the bioavailability
and pharmacokinetics of various formulations to more sophisticated mechanism-based approaches that delineate the relationship
between drug kinetics and various formulation or administration factors at the molecular level. Similarly, the evolution in
science and technology has provided regulatory scientists with opportunities to enhance the equivalence assessment of certain
products on a mechanistic basis from time to time. A prominent example is the regulatory application of the Biopharmaceutics
Classification System (BCS) that uses biopharmaceutical attributes (i.e., aqueous solubility and intestinal permeability)
for predicting bioavailability and bioequivalence (6). The waiver of in vivo bioequivalence studies for a BCS I drug (highly soluble and highly permeable) has been relied on the mechanistic rationing
that intrinsic gastric emptying (rather than formulation) is the "rate-limiting" step for in vivo delivery and absorption of the drug if it is formulated in a rapidly dissolving product.
Another example is cholestyramine resins for which in vitro equilibrium binding and in vitro kinetic binding studies have been used to determine bioequivalence by FDA (7). In essence, both in vitro assays use the resin's mechanism of action (i.e., binding of bile acid salts) to assess the binding behavior of different
formulations. Undoubtedly, the continued progress in science and technology will facilitate a greater characterization of
pharmaceutical attributes as well as better understanding of in vivo drug delivery and absorption processes so that more mechanism-based approaches can be used to establish therapeutic equivalence
between products. The following section provides theoretical considerations for bioequivalence assessment, which may shed
some light on how we can move forward in this area.