The United States Pharmacopeial Convention (USP) authorized the creation of an advisory panel to investigate the possibility of applying the principles of the Biopharmaceutics Classification System (BCS) to veterinary drugs—specifically, solid oral formulations administered to dogs (1). Developed for human pharmaceutical compounds (2, 3, 4, 5, 6), the BCS is an important tool that facilitates product development and regulatory decisions. By understanding the solubility of a compound in biorelevant media and its permeability across biological membranes, the rate limiting factors determining the rate and extent of oral drug absorption can be identified. This information can be invaluable for predicting the potential influence of formulation and physiological variables on oral drug bioavailability.

Within the framework of human pharmaceuticals, drugs can be classified into one of the following four BCS categories:

• Class I: high solubility, high permeability: generally very well-absorbed compounds

• Class II: low solubility, high permeability: exhibits dissolution rate-limited absorption

• Class III: high solubility, low permeability: exhibits permeability-limited absorption

• Class IV: low solubility, low permeability: very poor oral bioavailability

A complementary classification system was proposed by Wu and Benet (7, 8). They recognized that drugs exhibiting high permeability are generally extensively metabolized, while poorly permeable compounds are primarily eliminated as unchanged drug in the bile and urine. Thus, the Biopharmaceutical Drug Disposition Classification System (BDDCS) has been used to predict drug disposition and potential drug-drug interactions in the intestine and the liver and potentially the kidney and brain. Although the solubility criteria for the BCS and BDDCS are the same, there is a substantial difference in the second variable being considered. For the BDDCS, the second classification is related to the extent of drug metabolism. Conversely, the assessment of permeability in the BCS is linked to the extent of intestinal absorption, i.e., a drug is considered to be highly permeable when the extent of the systemic absorption (parent drug plus metabolites) in humans is determined to be at least 90% of an administered dose based on a mass balance determination or in comparison to an intravenous reference dose. Accordingly, the BCS and BDDCS classification of a drug may differ.

The US Food and Drug Administration’s (FDA’s) Center for Drug Evaluation and Research (CDER) (9) has incorporated BCS concepts into guidance documents for human medications into the 2000 FDA Guidance for Industry, including guidance for the waiver of in vivo bioequivalence study requirements for high solubility/high permeability drug products. However, the BCS has not as yet been extrapolated for application to veterinary drugs. The reason for this gap is that the BCS was developed based upon human digestive physiology, which can be vastly different from that observed in veterinary species. Given the similarity of therapeutic entities used in the dogs and humans, and because of the use of the dog as a preclinical species for human medicine (10), it would be of particular value to have an understanding of how the BCS criteria can be translated between human and canine gastrointestinal (GI) physiologies.

The solubility criteria used both by the BCS and the BDDCS rely upon formulation considerations in that it is based upon the highest dose that will be administered. Both the BCS and the BDDCS define a high solubility compound at the highest marketed dose strength that is soluble in 250 mL of water over the pH range of 1–7.5 at 37°C. This definition differs from that of “intrinsic solubility,” which reflects the equilibrium aqueous solubility of a compound. For acids and bases, intrinsic solubility represents the concentration of the unionized species in a saturated solution at the pH value where that compound is fully unionized (11). While there has been some debate regarding certain compounds whose intrinsic solubility may not be accurately defined when using conventional media (12, 13), those considerations are founded upon the perspective of a drug’s physicochemical characteristics rather than on the in vivo conditions into which that drug will be introduced. Thus, while intrinsic solubility is solely a function of the molecule, the BCS (or BDDCS)-based solubility criteria is dependent upon physiological conditions and the corresponding targeted therapeutic dose. Unfortunately, what constitutes the BCS-based criteria for high or low solubility is currently undefined for dogs because of complexities associated with interspecies differences in the composition of the GI milieu (1).

Another obstacle confronted when trying to establish canine-specific BCS criteria is the challenge associated with the classification of intestinal permeability. Despite the range of high throughput systems available for examining human intestinal permeability, such as Caco-2 cells, parallel artificial membrane permeability assay (PAMPA), and phospholipid vesicle-based permeation assay (PVPA), these methods for estimating drug permeability have only been applied to human drugs (14, 15). These systems have not been developed and validated for application to drug permeability across the canine intestine (16, 17). Moreover, while one may argue that transcellular permeability should be similar in humans and dogs, the GI tract of the dog tends to be more permeable (leakier) because of the larger intercellular pores (18).

Currently, the existing in vitro methods for evaluating drug permeability have not succeeded in providing data that can be extrapolated to dogs. For this reason, we needed to resort to comparisons based upon the use of absolute bioavailability. Because there are no suitable in vitro methods to assess effective permeability in dogs (Peff), we have used absolute bioavailability (F) for this analysis. We have justified this approach because a comparison of drug absorption across human colonic epithelium cell layers (Caco-2 cell line) to absorption across canine colon tissue did not show a relationship (19). The Ussing chamber technique, which has been evaluated for other veterinary species (20), has not been applicable for canine studies (21) because of the fragility of the tissue. Membrane damage that occurs prevents permeability measurements using this technique in dogs (21). Therefore, without the availability of these in vitro tools, other data must be used to predict permeability and apply BCS criteria for oral drugs administered to dogs.

The current investigation was undertaken because of the lack of established BCS criteria to evaluate oral medications administered to dogs. The objectives were to examine the properties that define human BCS criteria for drugs and to compare this information to pharmacokinetic data available from studies in dogs. Without in vitro intestinal permeability data in dogs, another parameter must be considered to classify a drug as either high or low permeability. To this end, there are numerous molecular factors that impact drug transcellular permeability, including hydrogen bonding properties, molecular size and shape, polarity, flexibility, and ionization properties (22, 23). There is no “gold standard” or [even a suggested criterion based upon the log of the lipophilicity coefficient (LogP) pH-dependent lipophilicity value (LogD)] that has been proposed as a cutoff value. Therefore, we focused on the use of the systemic absorption value (absolute bioavailability, F), which we were able to obtain from the published literature. It was assumed that if the value of F is high, permeability (via active or passive processes) must likewise be high. We also acknowledged at the outset that the converse was not necessarily true and that the use of F as an indicator of drug permeability will produce some false negative results, i.e., there are drugs that have high permeability, but low values of F because of other factors such as intestinal efflux or high first-pass metabolism.

A drug solubility classification has not been established for medications administered to dogs (24, 25). To classify a drug as either high or low solubility in dogs requires that one knows the ideal volume in which to measure solubility. In this study, we have examined two different volumes and considered whether this parameter can be useful to predict oral absorption of medications in dogs.

Ultimately, the objective of this study was to identify the in vitro drug properties with respect to their potential impact on dog-human differences and similarities on oral drug solubility and permeability. The foundational assumption was that if properties can be identified, we could then generate dog-specific criteria for applying BCS concepts to understand the critical formulation and physiological variables that can influence canine oral drug absorption. Similar to its tremendous influence on human drug product development and regulatory evaluation, a roadmap for screening oral product formulations, if applied to veterinary drug products, would provide a tool for screening new formulations. Additional benefits that would be associated with a canine-specific BCS would be an improvement on our ability to compare human formulations for potential testing and clinical use based upon information obtained in dogs (and vice versa).

One of our objectives was to extend our assessment beyond the results reported by Chiou et al., (26) in which the oral bioavailability of 43 compounds was compared in humans and dogs. In that study, they observed that while 22 of the 43 compounds were completely absorbed in both humans and dogs, the overall interspecies correlation of F values was low (coefficient of determination, R² = 0.51). A pitfall associated with the investigation by Chiou et al. was that much of the data were based upon radiolabeled data, thereby precluding a differentiation between parent compound and metabolites. Given the potential for interspecies differences in intestinal metabolism, and since F values were based on total urinary recovery of radioactivity of the drug (thereby further confounding the comparison with potential differences in post-absorption processes), we could not use that information to generate predictions on the permeability component of the BCS. However, we also recognized that a drug with a high first-pass effect may be reported with high F in the study by Chiou et al. (26), but not in our study reported. Thus, in addition to evaluation of BCS classification versus F in dogs and humans, we compared our F values with those reported by Chiou et al. (26).

The Biopharmaceutics Classification System is a system to differentiate the drugs on the basis of their solubility and permeability.^[1]

This system restricts the prediction using the parameters solubility and intestinal permeability. The solubility classification is based on a United States Pharmacopoeia (USP) aperture. The intestinal permeability classification is based on a comparison to the intravenous injection. All those factors are highly important because 85% of the most sold drugs in the United States and Europe are orally administered^{[citation needed]}.

BCS classes[edit]

According to the Biopharmaceutical Classification System (BCS) drug substances are classified to four classes upon their solubility and permeability:^[1]

• Class I - high permeability, high solubility
  • Example: metoprolol, paracetamol^[2]
  • Those compounds are well absorbed and their absorption rate is usually higher than excretion.
• Class II - high permeability, low solubility
  • Example: glibenclamide, bicalutamide, ezetimibe, aceclofenac
  • The bioavailability of those products is limited by their solvation rate. A correlation between the in vivo bioavailability and the in vitro solvation can be found.
• Class III - low permeability, high solubility
  • Example: cimetidine
  • The absorption is limited by the permeation rate but the drug is solvated very fast. If the formulation does not change the permeability or gastro-intestinal duration time, then class I criteria can be applied.
• Class IV - low permeability, low solubility
  • Example: Bifonazole
  • Those compounds have a poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and a high variability is expected.

Definitions[edit]

The drugs are classified in BCS on the basis of solubility, permeability, and dissolution.

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Solubility class boundaries are based on the highest dose strength of an immediate release product. A drug is considered highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous media over the pH range of 1 to 7.5. The volume estimate of 250 ml is derived from typical bioequivalence study protocols that prescribe administration of a drug product to fasting human volunteers with a glass of water.

Permeability class boundaries are based indirectly on the extent of absorption of a drug substance in humans and directly on the measurement of rates of mass transfer across human intestinal membrane. Alternatively non-human systems capable of predicting drug absorption in humans can be used (such as in-vitro culture methods). A drug substance is considered highly permeable when the extent of absorption in humans is determined to be 90% or more of the administered dose based on a mass-balance determination or in comparison to an intravenous dose.

For dissolution class boundaries, an immediate release product is considered rapidly dissolving when no less than 85% of the labeled amount of the drug substance dissolves within 15 minutes using USP Dissolution Apparatus 1 at 100 RPM or Apparatus 2 at 50 RPM in a volume of 900 ml or less in the following media: 0.1 N HCl or simulated gastric fluid or pH 4.5 buffer and pH 6.8 buffer or simulated intestinal fluid.

See also[edit]

• ADME

References[edit]

1. ^ ^abMehta M (2016). Biopharmaceutics Classification System (BCS): Development, Implementation, and Growth. Wiley. ISBN978-1-118-47661-1.
2. ^https://www.ema.europa.eu/documents/scientific-guideline/draft-paracetamol-oral-use-immediate-release-formulations-product-specific-bioequivalence-guidance_en.pdf

Further reading[edit]

• Folkers G, van de Waterbeemd H, Lennernäs H, Artursson P, Mannhold R, Kubinyi H (2003). Drug Bioavailability: Estimation of Solubility, Permeability, Absorption and Bioavailability (Methods and Principles in Medicinal Chemistry). Weinheim: Wiley-VCH. ISBN3-527-30438-X.
• Amidon GL, Lennernäs H, Shah VP, Crison JR (March 1995). 'A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability'. Pharm. Res. 12 (3): 413–20. PMID7617530.

External links[edit]

• BCS guidance of the U.S. Food and Drug Administration