Info

Class 3

Class 4

Low permeability

High solubility® Low permeability

Low solubility Low permeability

"Solubility is high when the highest dose strength is soluble in no more than 250 mL of aqueous media over the pH range 1 to 7.5.

bPermeability is considered high when total fraction absorbed is at least 90% or is measured in vitro to be higher than that of standard compounds.

°Class 1 drugs must have wide therapeutic index, and their dissolution must be rapid for an in vivo bioequivalence study to be waived. An immediate release product is considered rapidly dissolving when not less than 85% of the labeled amount of the drug substance is dissolved within 30 minutes of using USP Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a volume of 900 mL or less in each of the following media: 0. IN HC1 or simulated gastric fluid USP without enzymes, in a pH 4.5 buffer, and in a pH 6.8 buffer or simulated intestinal fluid USP without enzymes (29). Abbreviation: USP, U.S. Pharmacopeia. Source: From Refs. 29 and 84.

"Solubility is high when the highest dose strength is soluble in no more than 250 mL of aqueous media over the pH range 1 to 7.5.

bPermeability is considered high when total fraction absorbed is at least 90% or is measured in vitro to be higher than that of standard compounds.

°Class 1 drugs must have wide therapeutic index, and their dissolution must be rapid for an in vivo bioequivalence study to be waived. An immediate release product is considered rapidly dissolving when not less than 85% of the labeled amount of the drug substance is dissolved within 30 minutes of using USP Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a volume of 900 mL or less in each of the following media: 0. IN HC1 or simulated gastric fluid USP without enzymes, in a pH 4.5 buffer, and in a pH 6.8 buffer or simulated intestinal fluid USP without enzymes (29). Abbreviation: USP, U.S. Pharmacopeia. Source: From Refs. 29 and 84.

The Biopharmaceutics Classification System

The concept of BCS is that immediate release drug products containing the same dose of the same drug substance, and having the same intralumenal dissolution and gut wall permeability profiles in vivo, will be bioequivalent. Although the concept has received wide acceptance worldwide, there are difficulties in measuring the parameters of interest, which most frequently refer to the small intestine, because drug absorption takes place primarily in this region.

Although both invasive (86) and noninvasive (87) methods have been proposed, measurement of dissolution intralumenally is not practical and, at best, existing methods require further validation. As a result, to date, intralumenal dissolution is mostly assessed with in vitro setups that simulate (to a certain degree) the intralumenal environment (29,88). Since direct correlation of in vitro dissolution data with intralumenal dissolution data is, to date, not practical to achieve, attempts are being made to estimate intralumenal dissolution from intralumenal solubility data that can be collected relatively easier (89-92). However, intralumenal solubility data may not be directly proportional to intralumenal dissolution data (89), because solubility is only one of the parameters affecting dissolution. For example, intralumenal hydrodynamics (that to date are only poorly simulated in vitro) play a significant role (93).

In regard to permeability of the epithelium of the small intestine, although it can be measured in humans (94), associated costs are extremely high. Thus, permeability estimations are typically based on in vitro data [most frequently collected by using cell monolayers developed from human colonic carcinoma epithelia (e.g., the Caco-2 cell lines)] or in situ animal data (most frequently collected by perfusing segments of rat small intestine). However, Caco-2 cell lines are associated with overexpression of certain transporters, and they do not allow for paracellular transport. In addition, correlations of either Caco-2 data with human data or rat perfusion data with human data are highly scattered. Alternative methodologies for assessing permeability are also not free of drawbacks. For example, decision on high or low permeability based on the total percentage of dose absorbed in humans (Table 1) has two weaknesses. First, the extent of absorption is used as surrogate of a kinetic parameter, permeability. Second is that if first pass metabolism is substantial, it would complicate the estimation of total percentage of dose absorbed. Recently, it has been suggested that drugs that are extensively metabolized are highly permeable drugs and regulatory agencies should add the extent of drug metabolism (i.e., >90% metabolized) as an alternate method for the extent of drug absorption (i.e., >90% absorbed) (95). Even this approach, however, has some drawbacks. For example, permeable drugs that are excreted unchanged into urine or bile may be incorrectly classified as lowly absorbed compounds, whereas drugs such as amoxicillin, chloroquine, lomefloxacin, trimethorpin, and zalcitabine that exhibit >90% oral bioavailability will also be listed as poorly absorbed drugs (96).

Biowaivers* Based on the Biopharmaceutics Classification System

Despite the problems associated with the correct classification of compounds according to the BCS, the current approach in deciding high solubility and high permeability compounds is considered a conservative and, therefore, safe approach (Table 1) (29,85). Using this approach, biowaivers could be granted for high solubility-high permeability

"Generic drug products approvals without in vivo bioequivalence studies.

drugs, whereas possible extensions of biowaivers in other classes are currently being considered.

According to the relevant guidance launched in 2000 by the FDA (29) and subsequently adapted by other regulatory bodies worldwide (85), biowaivers can be requested and granted for drug substances that do not have a narrow therapeutic index, belong to BCS class 1, and are housed in rapidly dissolving immediate release products (Table 1). If these criteria are met, the drug absorption process is controlled by gastric emptying and, therefore, formulation differences are not expected to play a role.

Class 1 drugs represent a subset of drugs that is decreasing with time: If the orally administered immediate release products in the List of Essential Medicines of the World Health Organization (WHO) are considered, approximately 30% can be considered as class 1 drugs (97,98). However, the proportion of class 1 compounds in the development phase for oral immediate-release formulations at AstraZeneca was less than 10% in 2001 (99), and is slightly less than 20% at GlaxoSmithKline (100).

The percentage of drugs belonging to class 2 is steadily increasing (96,100), and there is growing interest in identifying situations within this class that can be considered for waiving an in vivo BE study. It has been suggested that acidic drugs that belong to class 2 that show low solubility in the stomach and high solubility in the upper small intestine could be granted biowaivers (101,102). An approach for waiving an in vivo BE study of weakly acidic class 2 compounds has been recently proposed by the WHO on the basis of the rapid dissolution characteristics in slightly acidic pH values (simulating the pH conditions of the upper small intestine) (103). However, other studies suggest that, although in vitro testing of this type of drugs could predict differences between two products on the extent of absorption, differences on the maximum plasma concentration may not be predicted with in vitro testing as these may additionally be affected by intragastric solubility, gastric emptying, and type of formulation (104). Therefore, at present time, there are no widely accepted procedures for granting biowaivers to class 2 drugs.

Since permeability of a class 3 drug through the gut wall is the rate-determining step for the overall absorption process, formulation effects are expected to play a less important role in drug absorption, and, consequently, biowaivers have been suggested to be granted to compounds belonging to this class (105-107). For passively absorbed class 3 drugs, one issue is that permeability might be location dependent, i.e., it is likely that will fall to low values in the distal small intestine. This issue could be overcome with the development of rapidly dissolving formulations to obtain the best possible absorption (103). Another issue for passively absorbed drugs is the potential excipients' effects on permeability. Conventional excipients at commonly used amounts have been shown not to be critical with regard to the absorption of atenolol (108), cimetidine (109), and ranitidine (110) in humans. However, it should be underlined that other excipients can have pronounced effects on the absorption of these drugs (111,112). Finally, class 3 compounds for which their absorption in humans has been convincingly shown to involve the participation of certain carriers should be very cautiously considered for granting biowaivers, since excipients' effects on this type of transport may be even more difficult to predict (113).

Was this article helpful?

0 0

Post a comment