Liposome Drug Products: Bioavailability and Bioequivalence Issues

Kofi A. Kumi, R.Ph., Ph.D.Office of Clinical Pharmacology and BiopharmaceuticsDivision of Pharmaceutical Evaluation IIIACPS 7/20/2001

Bioavailability

Regulatory 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.”

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….”

Bioavailability/Bioequivalence

Key factors for consideration in assessing bioavailability (BA) and bioequivalence (BE) of liposome drug products

Release of active moiety from drug product

Availability at the site of action

Types of Evidence to EstablishBA/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:

Blood/plasma/serum drug conc. measurement in humans Urinary excretion in humans In vivo pharmacological effect Well-controlled clinical trials In-vitro test Any other approach deemed adequate by FDA

Prerequisites for Using PK Method to Assess BA/BE

Availability of a specific and sensitive analytical method useful when determining in vivo release of drug from liposomes Rate of release of drug from carrier affects

overall pharmacokinetics (PK) of drug and carrier

Demonstrating in vivo stability (Pilot) 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.

Classification of Liposome Drug Products Based on MPS

Mononuclear Phagocyte System (MPS)

= Reticuloendothelial system (RES)

MPS Uptake

MPS Avoidance

Intermediate

MPS Uptake Liposomes

Preferential uptake (targeted) by MPS Relatively short duration in systemic

circulationGenerally, active drug slowly released

back into systemic circulation from depot site (MPS)

PK dose-dependentPK affected by particle size, charge, etc.

MPS Avoidance Liposomes

Designed to evade recognition and uptake by MPS

Remain in systemic circulation for extended period

Preferential uptake (“targeting”) at site(s) other than MPS

PK dose-independentPK affected by liposome composition,

charge, etc.

The Key Issues

Is blood/plasma/serum concentration of drug adequate to determine BA and BE in view of the fact that

Liposome drug products (LDP) may or may not be stable in vivo

The residence time of the LDP in the blood/ serum/plasma may differ

Different LDPs may be designed targeted toseparate sites

e.g. MPS, Tumor cells

MPS Uptake: Suggested Scheme for BA/BE Determination

Measurem ent of total drug conc.

Yes

PD m easures orC linical endpoints

No

Stable in vivoprior to uptake?

MPS-Uptake

Liposom e Drug Products

MPS Avoidance: Suggested Scheme for BA/BE Determination

Total drug conc.

Yes

Separate m easurem ents ofencapsulated and unencapsulated

drug conc.

No

Stable in vivo?

Yes

PD m easures orC linical endpoints

No

Drug conc. m easurem ents?

MPS-Avoidance

Liposom e Drug Products

Combined Scheme for Determination of BA/BE

Total drug conc.

Yes

Separate m easurem ent ofencap. and unencap.

drug conc.

No

Stable in vivo?

Yes

PD m easures orClinical endpoints

No

Drug conc. m easurem ent?

MPS-Avoidance

Case by caseMode and site of

action, etc

Interm ediate

Measurem ent of total drug conc.

Yes

PD m easures orClinical endpoints

No

Stable in vivoprior to uptake?

MPS-Uptake

Liposom e Drug Products

Acknowledgements

Mei-Ling ChenHelen WinkleBarbara Davit Ajaz HussainArthur Shaw Yuan Yuan ChiuLiposome WG members Larry Lesko

John LazorArzu SelenFunmi AjayiMehul MehtaHae-Young AhnCDS CC membersDPEIII colleagues