Therapeutic goals and challenges in developing liposomal parenterals

Peter LangguthPharmazeutische Technologie und Biopharmazie

J. Gutenberg University Mainz, FRG

3rd Symposium on Harmonization of BE Requirements, Amman (2018)

Graphic from Jesorkar and Owar

The Tools of Nanomedicine

- 1964: Discovery of liposomes – Alec Bangham (Cambridge, UK)

- 1971: First in vivo applications of liposomes for drug delivery

- 1982: Liposomes to reduce cardiac toxicity of doxorubicin (Dox)

- 1991-92: 1st tests of Peg-Lip-Dox in humans

- 1995: US-FDA first approval of Peg-Lip-Dox for cancer therapy

- Today: At least 8 liposome formulations FDA/EMA-approved for cancer therapy (6/8 considered nanomedicines)

Liposomes remain a versatile drug delivery technology leading the Nanomedicine field

Liposomes as Pioneers in the Field of Nanomedicine

Liposome and Liposome Drug Products

Microvesicle composed of a bilayerand/or a concentric series of multiplebilayers separated by aqueouscompartments formed by amphipathicmolecules such as phospholipids thatenclose a central aqueous compartment

A drug product in which the activepharmaceutical ingredient (API) iscontained in liposomes

Liposome

Liposome Drug Product

Lipids & Phospholipids (Selection)

Liposome Drug Products are Versatile

Sizes

Administration routes

Indications

Delivery modes

Active pharmaceuticalingredients

Nanometer to Micrometer

Intravenous, Intrathecal, Epidural

Cancer, certain fungal infections, age‐related macular degeneration, and pain

Immediate, sustained and/or targeted

Hydrophilic and hydrophobic Single or multiple

Complexity of Liposome Drug Products and Regulatory Guidances

Tissue uptake of liposome drug productAPI release/leakagefrom liposomesClearance of released/ unbound APIClearance of liposomedrug productClearance of liposomedrug carrier

In vivo processes

Recommendations for in vivo PK and BA Studies for Parenteral Liposome Drug Products

For new drug application (NDA) of liposome drug products

• Pharmacokinetic and Mass Balance Studies for Liposome Drug Products‐ Multiple‐dose study evaluating the drug pharmacokinetics after administration of the liposome drug product

‐ Dose‐proportionality study over the expected therapeutic dose range of the liposome drug product

‐ Exposure‐response studies if available

• Compare liposome drug products to the corresponding approved nonliposomeformulation to elucidate differences in absorption, distribution, metabolism, andexcretion (ADME)

Guidance for Industry. Liposome drug products, chemistry, manufacturing, and controls; human pharmacokinetics and bioavailability; andlabeling documentation. U.S. Food and Drug Administration. https://www.fda.gov/downloads/drugs/guidances/ucm070570.pdf (2018)

FDA Approved Liposome Drug ProductsTrade name Active

ingredientIndication Route Initial 

Approvaldate

Market statusavailable

Doxil DoxorubicinHCl

Ovarian cancer, AIDS‐related Kaposi’ssarcoma, multiple myeloma

Intravenous 11/17/1995 Yes

DAUNOXOME Daunorubicincitrate

Advanced HIV‐related Kaposi’s sarcoma(relapse)

Intravenous 04/08/1996 yes

AMBISOME AmphotericinB Certain fungal infections Intravenous 08/11/1997 Yes

DEPOTCYTE Cytarabine Lymphomatous meningitis Intrathecal 04/01/1999 Discont.

Visudyne Verteporfin Photosensitizer Intravenous 04/12/2000 Yes

DEPODUR Morphine SO4 Opioid local analgesic Epidural 05/18/2004 Discont.

EXPAREL Bupivacaine Postsurgical analgesia Surgical site 10/28/2011 Yes

MARQIBO Vincristine SO4 Acute lymphoblastic leukemia Intravenous 08/09/2012 Yes

ONIVYDE Irinotecan HCl Metastatic pancreatic cancer Intravenous 10/22/2015 Yes

VYXEOS Daunorubicinand Cytarabine

Therapy‐related acute myeloid leukemia (t‐AML) or AML with myelodysplasia‐relatedchanges (AML‐MRC)

Intravenous 08/03/2017 yes

https://www.accessdata.fda.gov/scripts/cder/daf/

Age‐Related Macular Degeneration

Verteporfin Liposome Injection• Proprietary name: Visudyne

• Generic name: Verteporfin Liposome Injection

• Indication and Regimen:Age‐related macular degeneration in patients with predominantly classic subfoveal choroidal neovascularization

Verteporphin: Preclinical/clinical PK findings

In vitro release studies

Clinical pharmacokinetic study

Preclinical tissuedistribution study

No drug retention after iv administration; liposomesfunction as vehicle only

Immediate and complete transfer of verteporfin from liposomes to plasma proteins and lipid vesicles.

Relatively large volume of distribution of liposomal verteporfin (0.6 L/kg) and a high plasma protein binding (90%), indicating an extensive extravascular distribution of released verteporfin.

Liposome formulation of Visudyne did not cause accumulation of verteporfin in mouse liver, lung and spleen• Negligible reticulo‐endothelial system (RES) uptake ofverteporfin after i.v. administration of Visudyne whencompared with DMSO solubilized verteporfinCancer, certain fungal infections, age‐related macular degeneration, and pain

Chowdhary RK et al. Drug release characteristics of lipid based benzoporphyrinderivative. Journal of Pharm. Pharmaceut. Sci. (2003) 6 (1): 13‐19

Verteporfin LiposomeInjection

Liposome classification system for characterization of liposome drug products*

From: Hsu L and Huang J, Int J Clin Pharm Therap, 2014