BCS-Based Biowaiver Monographs Prof. Dr. Jennifer Dressman & Corina Becker Johann Wolfgang Goethe University Frankfu

1. Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutics Classification BCS-Based Biowaiver Monographs Prof. Dr.Jennifer Dressman & Corina Becker Johann Wolfgang Goethe University Frankfurt am Main, Germany

2. The WHO Biowaiver Procedure Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms. Technical Report Series, No 937, 40th Report, Annex 8 of WHO Expert committee on specifications for pharmaceutical preparations Scope • Simplified approval for IR generic solid oral products Demonstration of BE by in vitro instead of in vivo PK Studies Advantage

3. The Biowaiver Monographs I. • An initiative of the Federation Internationale Pharmaceutique (FIP). • The aim is to summarize all data from the literature relevant to the decision as to whether dissolution can be used as a surrogate for PK to show bioequivalance. • The biowaiver procedure can be used to demonstrate bioequivalence after a product has been scaled-up, in the approval of a new, multisource product of an existing API, and in continued approval of products for which there has been a change in composition and/or manufacturing procedure.

4. The Biowaiver Monographs II. • The approach includes all factors considered in the WHO Document: „Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms.” Technical Report Series, No 937, 40th Report, Annex 8 of WHO Expert committee on specifications for pharmaceutical preparations • Where criteria vary among various regions (US, EU), these are also addressed. • A recommendation is given about whether the biowaiver procedure can be utilized, or if bioequivalence should rather be tested with a pharmacokinetic comparison.

5. BiowaiverCriteria • l BCS Biowaiver • Risks • Therapeutic Index • Indication Dissolution • Interactions with Food and Excipients • BA/BE Studies

6. The Biowaiver MonographWhat is taken into consideration? Physicochemical properties, especially solubility at 37°C between pH 1.2 and 6.8, but also pKa, logP, polymorphism, solvates and saltsIf necessary, additionaly solubility and dissolution studies are run with the pure API Therapeutic indications, therapeutic index, types and severity of toxic effects observed. Literature and laboratory data comparing dissolution of existing products Determinations of Permeability e.g. BAabs, urinary excretion, Caco-2 studies Literature studies on bioequivalence of existing products Interactions with food and excipients

7. The Biopharmaceutics Classification System U.S. Department of Health and Human Services Food and Drug Administration Center for Evaluation and Research (CDER). 2000. Guidances for industry: Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System Highly permeable II I Highly soluble Poorly soluble III IV Poorly permeable

8. BCS Criteria according to WHO Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms. Technical Report Series, No 937, 40th Report, Annex 8 of WHO Expert committee on specifications for pharmaceutical preparations Permeability Solubility • Dose/Solubility ratio ≤ 250 ml • in 3 aqueous media pH 1.2 – 6.8 • 37°C • Absorption ≥ 85 % • Human absolute BA or mass balance studies • alternatives are intestinal perfusion and tissue permeation studies BCS

9. Case Example: Pyrazinamide • One of the four main APIs used in treatment of Tubercolosis • Its highly specific action against mycobacterium tuberculosis in an acid environment contributes important sterilizing activity to the standard chemotherapy • The most common, serious adverse effect is liver damage, which occurs in 15% of patients at doses just above the therapeutic range.

10. Solubility of Pyrazinamide • in compendial buffers pH 1.2 – 6.8 at 37°C,equilibrium solubility after 24 hours Highly soluble D/S ratio 17.6 ml D/S ratio 18.6 ml D/S ratio 18.0 ml

11. Permeability of Pyrazinamide • 34% Urinary recovery of a oral dose after 24 h, 40% after 48 h Ellard GA 1969. Absorption, metabolism and excretion of pyrazinamide in man. Tubercle 50(2):144-158. • Urinary recovery of 73% after 72 h 0- 4% fecal recovery Lacroix C, Hoang TP, Nouveau J, Guyonnaud C, Laine G, Duwoos H, Lafont O 1989. Pharmacokinetics of pyrazinamide and its metabolites in healthy subjects. Eur J Clin Pharmacol 36(4):395-400. • Pyrazinamide is actively reabsorbed in the kidney Weiner IM, Tinker JP 1972. Pharmacology of pyrazinamide: metabolic and renal function studies related to the mechanism of drug-induced urate retention. J Pharmacol Exp Ther 180(2):411-434. • Kasim et al.  BCS III Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennernas H, Hussain AS, Junginger HE, Stavchansky SA, Midha KK, Shah VP, Amidon GL 2004. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol Pharm 1(1):85-96. • Lindenberg et al.  BCS III Lindenberg M, Kopp S, Dressman JB 2004. Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system. Eur J Pharm Biopharm 58(2):265-278. • WHO Guideline für bioequivalence  BCS III/I WHO 2006. Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms. Technical Report Series, No 937, 40th Report, Annex 8 of WHO Expert committee on specifications for pharmaceutical preparations. „Poorly permeable“

12. Dissolution of existing products, literature studies of Bioequivalence 120 100 80 60 % dissolved 40 20 0 0 10 20 30 time [min] • No cases of bioINequivalence reported in the literature • Products on German market have similar dissolution profiles • “Very rapidly • dissolving” • 400 mg pure substance • Pyrafat® • Pyrazinamide “Lederle”

13. Evaluation of the collected Information • BCS Class (II, III, IV) • narrow therapeutic index • „critical“ indication • Risk of abuse • slow and incomplete dissolution • „Food effects“ or interaction with excipients • published bioinequivalence • BCS Class I (II, III) • wide therapeutic index • „uncritical“ indication • no risk of abuse • „rapid“ or „very rapid“ dissolution • no reported interaction with food or excipients • BE- Studies - Biowaiver +

14. Biowaiver Recommendation for Pyrazinamide 20 18 16 14 12 10 8 6 4 2 0 120 100 80 % dissolved 60 40 20 0 0 10 20 30 time [min] BCS Class Solubility Permeability III • 73% Urinary excretion after 72h • no recovery in the feces • Dose-proportional absorption in range 200 – 3600 mg Solubility > 20 mg/ml D/s ratio < 20 ml 400mg Biowaiver Only withspecific requirements for monitoring hepatic function • Indication: Long-term treatment of TB • Toxicity: Hepatoxicity • Monitoring of hepatic function • Inhibition of urate excretion (gout) • “Very rapidly • dissolving” • 400 mg pure substance • Pyrafat® • Pyrazinamide “Lederle” Dissolution Risks

15. Summary of biowaivers for first line anti-TB drugs

16. Biowaiver Monographs already available • Isoniazid • Prednisolone • Prednisone • Propanolol • Ranitidine • Verapamil • Acetaminophen (Paracetamol) • Amitriptyline • Atenolol • Chloroquine • Cimetidine • Ethambutol • Ibuprofen www.fip.org/bcs

17. Many thanks to the team of co-authors • Dirk Barends (rivm Holland), Chief Editor • Jennifer Dressman (University of Frankfurt), Co-Editor • Gordon Amidon • Vinod Shah • Kamal Midha • Solomon Stavchansky • Sabine Kopp (WHO) • Hans Junginger…………………………and the many first authors who give their time and expertise to the project!