1. 1 The Biopharmaceutical Classification System (BCS) Dr Mohammad Issa

2. 2 Biopharmaceutical Classification System (BCS)  Biopharmaceutics Classification System (BCS) is a predictive approach to relate certain physicochemical characteristics of a drug substance and drug product to in-vivo bioavailability  BCS categorized drugs according to two key physico-chemical parameters: Solubility Permeability

3. 3 Biopharmaceutical Classification System (BCS)  These two factors were selected because most orally administered drugs are absorbed via a passive diffusion process through the small intestine, where the extent of oral absorption is largely influenced by a drug’s membrane permeability and solubility

4. 4 BCS Classes Class I Highly permeable Highly soluble Class II Highly permeable Poorly soluble Class III Poorly permeable Highly soluble Class IV Poorly permeable Poorly soluble

5. 5 Biopharmaceutical Classification System (BCS)  According to the FDA guidelines, a high solubility drug is defined as one that, in the largest dose strength, fully dissolves in 250 mL of aqueous medium with the pH ranging from 1 to 7.5 at 37 ° C. Otherwise, drugs are considered poorly soluble. In other words, the highest therapeutic dose must dissolve in 250 mL of water at any physiological pH  In the same guidance as mentioned above, a drug is considered highly permeable if the extent of oral absorption is greater than 90%

6. 6 Biopharmaceutical Classification System (BCS) objectives  to guide decisions with respect to in vivo and in vitro correlations and the need for bioequivalence studies  to provide a useful framework to identify appropriate dosage form designs that are aimed at overcoming absorption barriers posed by solubility and permeability related challenges

7. 7 BCS Class I: High Solubility and High Permeability  Compounds belonging to this class are normally expected to dissolve quickly in gastric and intestinal fluids, and readily cross the intestinal wall through passive diffusion  BCS Class I are unlikely to show bioavailability or bioequivalence issues  Therefore, for BCS class I drugs, in vitro dissolution studies are thought to provide sufficient information to assure in vivo product performance making full in vivo bioavailability / bioequivalence studies unnecessary

8. 8 BCS Class I: High Solubility and High Permeability  Although class I compounds are expected to have excellent oral absorption, given their high solubility and high permeability, additional absorption barriers may exist beyond the scope of the BCS  For example, luminal complexation and degradation can significantly limit the amount of drug available for absorption. Even after the drug crosses the intestinal membrane, it may be metabolized within the enterocytes/hepatocytes and/or pumped out of the cells due to efflux mechanisms.

9. 9 BCS Class II: Poor Solubility and High Permeability  By definition, poor solubility and/or slow dissolution are the rate-limiting steps for oral absorption of BCS class II compounds  For compounds with a very large dose-to- solubility ratio, poor solubility is likely to be the rate-limiting step for absorption.  In other words, the compounds may dissolve quickly enough to reach their equilibrium solubility, but the solubility is too low to establish a wide enough concentration gradient to drive passive diffusion

10. 10 BCS Class II: Poor Solubility and High Permeability  Formulations designed to overcome solubility or dissolution rate problems: Salt formation Particle size reduction Metastable forms Solid dispersion Complexation Lipid based formulations Precipitation inhibitors

11. 11 BCS Class III: High Solubility and Low Permeability  Since passive diffusion is the rate- limiting step for oral absorption of BCS class III compounds, the most effective way to improve absorption and bioavailability of this class of compounds is to increase the membrane permeability  Approaches to improve permeability: Prodrugs Permeation enhancers

12. 12 BCS Class IV: Low Solubility and Low Permeability  Class IV compounds exhibit both poor solubility and poor permeability, and they pose tremendous challenges to formulation development  As a result, a substantial investment in dosage form development with no guarantee of success should be expected  A combination of class II and class III technologies could be used to formulate class IV compounds, although the success rate is not expected to be high

13. 13 Case Study I: Use of the BCS in Formulation Development  Pregabalin (Lyrica®) is is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy, management of postherpetic neuralgia, adjunctive therapy for adult patients with partial onset seizures, and management of fibromyalgia  Pregabalin is a BCS Class 1 compound (highly permeable and highly soluble). Pregabalin is an amino acid and its lowest aqueous solubility occurs at its isoelectric point (at pH 7.4)

14. 14 Case Study I: Use of the BCS in Formulation Development  It is considered high solubility as the amount of water needed (<10 mL) to dissolve the highest dose strength (300 mg) at pH 7.4 is less than the 250 mL criteria. Pregabalin meets the BCS criteria for a highly permeable compound as greater than 90% of the dose is excreted unchanged in the urine  Three different series of formulations were used during clinical development. Each series was comprised of one to three different dose strengths. Strengths within each series were content proportional with respect to drug and excipients

15. 15 Case Study I: Use of the BCS in Formulation Development  All three series used the same excipients; however the relative proportion of each excipient was different for each series  Bioequivalence between and among these formulations and the commercial formulation was established for this BCS Class 1 compound by demonstrating that all formulations were rapidly dissolving and had similar dissolution profiles over a pH range of 1.2 to 6.8  Thus bioequivalence was demonstrated using dissolution data and waivers of in vivo bioequivalence studies were granted

16. 16 Case Study I: Use of the BCS in Formulation Development  Application of BCS had significant impact on the cost of clinical development program for pregabalin.  It has been estimated that this example saved the company more than $1,000,000 compared to a more traditional approach that would have utilized four separate bioequivalence studies  Further, indirect savings are equally impressive. Considering that yearly Pregabalin sales exceed $1,200,000,000, each month of times saving equates to an additional $100,000,000 in sales prior to loss of patent exclusivity

17. 17 Modifications to BCS classification  A major limitation of the BCS is that it does not provide an in-depth understanding of how drug metabolism and drug transport may impact the pharmacokinetic performance of drug products  In 2005, Wu and Benet proposed a modified version of classification system— the biopharmaceutical drug disposition classification system (BDDCS)

18. 18 Biopharmaceutical Drug Disposition Classification System (BDDCS)  After reviewing 130 drugs listed in the WHO Essential Medicines List in terms of their solubility, permeability, and pharmacokinetic parameters, they found a common theme linked the BCS to drug metabolism.  The high permeability of BCS class I and II compounds allows ready access to the metabolizing enzymes within hepatocytes. Therefore, compounds in classes I and II are eliminated primarily via metabolism  Compounds in classes III and IV have low permeability, and are primarily eliminated unchanged into the urine and bile

19. 19 Biopharmaceutical Drug Disposition Classification System (BDDCS) BDDCS class I  High solubility  Extensive metabolism (Rapid dissolution and 70% metabolism for biowaiver) BDDCS class II  Low solubility  Extensive metabolism BDDCS class III  High solubility  Poor metabolism BDDCS class IV  Low solubility  Poor metabolism

20. 20 BDDCS advantages  May provide a useful framework to predict effects of food, enzyme transporter interplay, and drug–drug interactions on the pharmacokinetic performance of drug products  it is easier to obtain accurate metabolism data than permeability data  BDDCS could provide a useful framework to predict drug disposition profiles, as well as to expand the number of class I compounds eligible for waiver of in vivo bioequivalence study

21. 21 BDDCS for predicting transporter effect on oral absorption High solubility and high permeability of class I compounds allows a high concentration in the gut to saturate both the absorptive and efflux transporter. As a result, transporters will not play a significant role affecting oral absorption of class I compounds.

22. 22 BDDCS for predicting transporter effect on oral absorption The high permeability of class II compounds allows their ready access across the gut membrane, and implies that absorptive transporters will not have an effect on absorption. But their low solubility prevents saturation of the efflux transporter, resulting in the dominant effect of efflux transporters on oral absorption of this class of compounds.

23. 23 BDDCS for predicting transporter effect on oral absorption The low permeability/high solubility of class III compounds indicates that an absorptive transporter will affect the extent of oral bioavailability and rate of absorption of the class III compounds. Both the absorptive and efflux transporters could have a significant effect on oral absorption of class IV compounds.

24. 24