1. Liposome Drug Products: Bioavailability and Bioequivalence Issues Kofi A. Kumi, R.Ph., Ph.D. Office of Clinical Pharmacology and Biopharmaceutics Division of Pharmaceutical Evaluation III ACPS 7/20/2001

2. Bioavailability uRegulatory Definition (21 CFR 320.1(a)): “Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.”

3. Bioequivalence  Regulatory Definition (21 CFR 320.1(e)): “ Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study ….”

4. Bioavailability/Bioequivalence uKey factors for consideration in assessing bioavailability (BA) and bioequivalence (BE) of liposome drug products sRelease of active moiety from drug product sAvailability at the site of action

5. Types of Evidence to Establish BA/BE 21 CFR 320.24 The following in vivo and in vitro approaches, in descending order of accuracy, sensitivity, and reproducibility, are acceptable for determining the bioavailability or bioequivalence of a drug product: uBlood/plasma/serum drug conc. measurement in humans uUrinary excretion in humans uIn vivo pharmacological effect uWell-controlled clinical trials uIn-vitro test uAny other approach deemed adequate by FDA

6. Prerequisites for Using PK Method to Assess BA/BE u Availability of a specific and sensitive analytical method useful when determining in vivo release of drug from liposomes s Rate of release of drug from carrier affects overall pharmacokinetics (PK) of drug and carrier u Demonstrating in vivo stability (Pilot) s Separate measurement of encapsulated (E) & unencapsulated (U) drug in an in vivo single dose study. If the drug remains in the circulation substantially in the E form and the ratio of U/E remains constant, then the liposome drug product may be considered stable in vivo.

7. Classification of Liposome Drug Products Based on MPS u Mononuclear Phagocyte System (MPS) = Reticuloendothelial system (RES) s MPS Uptake s MPS Avoidance s Intermediate

8. MPS Uptake Liposomes uPreferential uptake (targeted) by MPS uRelatively short duration in systemic circulation uGenerally, active drug slowly released back into systemic circulation from depot site (MPS) uPK dose-dependent uPK affected by particle size, charge, etc.

9. MPS Avoidance Liposomes uDesigned to evade recognition and uptake by MPS uRemain in systemic circulation for extended period uPreferential uptake (“targeting”) at site(s) other than MPS uPK dose-independent uPK affected by liposome composition, charge, etc.

10. The Key Issues u Is blood/plasma/serum concentration of drug adequate to determine BA and BE in view of the fact that sLiposome drug products (LDP) may or may not be stable in vivo sThe residence time of the LDP in the blood/ serum/plasma may differ sDifferent LDPs may be designed targeted to separate sites  e.g. MPS, Tumor cells

11. MPS Uptake: Suggested Scheme for BA/BE Determination

12. MPS Avoidance: Suggested Scheme for BA/BE Determination

13. Combined Scheme for Determination of BA/BE

14. Acknowledgements Mei-Ling ChenHelen Winkle Barbara DavitAjaz Hussain Arthur ShawYuan Yuan Chiu Liposome WG membersLarry Lesko John Lazor Arzu Selen Funmi Ajayi Mehul Mehta Hae-Young Ahn CDS CC members DPEIII colleagues