Nanosize: What Can We Learn about Nonclinical Evaluations? Abby - - PowerPoint PPT Presentation

Nanosize: What Can We Learn about Nonclinical Evaluations?

Abby Jacobs CDER/FDA 1/2014 NOT official CDER/FDA policy

The Interplay Between Characterization and Toxicology (a)

• How do we know the material has been made

reproducibly?

• How do we know that the material is

representative of what humans will be exposed to?

• What are all the different factors, vehicles, and

media that affect the aggregation and surface properties of the drug– in vitro and in vivo?

The Interplay Between Characterization and Toxicology (b)

• How should the dose in a nonclinical study be

described?

• Not only mg/kg or mg/m2
• Surface properties
• Protein binding properties
• Since there is always a particle size

distribution, to what particle size range should we attribute various biologic effects?

Particle Properties (a)

• Changes in which properties could affect

biologic properties?

• Slight differences in physical properties

could impact tox

Particle Properties (b)

• Biodegradable carrier vs NON

biodegradable

• Water soluble carrier vs NON water

soluble

• Stability/aggregation at stomach pH
• Stability/aggregation in blood
• Stability/aggregation under in vitro

conditions

Route-specific Issues (a)

• Inhalation

– Local/respiratory toxicity – Distribution in respiratory tissues – Systemic bioavailability

• SC

– Sensitization

Route-specific Issues (b)

• Dermal

– Dermal and systemic bioavailability – Increased hair follicle penetration – Distribution to local lymph nodes – Different effects in sunlight (TiO2 and ZnO sunscreens)

Route-specific Issues (c)

• IV

– Liposome may have different tissue distribution and longer half-life of API – Hemocompatability – Sterility

• Ocular

– Intravitreal retention

Route-specific Issues (d)

• Oral
• Increased bioavailability for milled products
• Other than possible local effects and an

increased absorbed dose, if the original tox studies were adequate, new effects are not expected

– Drugs may interact with receptors at the single molecule level, so particle size would not be expected to play a role

Where Do the Various Parts of Particle Products Go (a)?

• Can drug components and or carrier now cross

the blood brain barrier?

• Reach the fetus when it didn’t previously?
• Enter other cells when it didn’t previously–

and stay there?: erythrocytes

• What types of assays, short of in vivo studies,

could be used to address some of these questions?

Where Do the Various parts of Particle Products Go (b)?

• Internalization by tumor cells?
• Accumulate in spleen or other tissues?
• Does tissue/cellular distribution change

with differences in particle size between 10 and 100 nm?

• Will it be case by case?

Are Standard Tests (ADME and Tox) and Route-Specific Studies Sufficient (a)?

• New products, carriers, linkers or

combinations vs milled previously marketed products of larger particle size

• New products would be thoroughly tested
• How much testing is needed for milled versions
• f previously tested and marketed products?

– ADME and a tox bridging study?

Are Standard Tests (ADME and Tox) and Route-Specific Studies Sufficient (b)?

• Are there any situations/product types for

which a standard tox studies in conjunction with tissue distribution studies, including to the placenta/fetus, would be insufficient?

• Thus far we have no such examples

Are Standard Tests Sufficient?

• For multifunction combination

component particles, is it sufficient to test the entire product or should separate NME components also be tested at a single high dose?

In Vitro Tests (a)

• Which ones could give meaningful

information and when?

– If particle has insoluble components? – If particles aggregate under in vitro conditions differently than under in vivo conditions?

• Some in vitro assays suggest problems not

seen in vivo (by respiratory and dermal routes of administration)

In Vitro Tests (b)

• Are any of the tests used for medical

devices helpful?

– Biocompatability for inert carriers? – Cytotoxicity?

• Perhaps as a screen by the developer of

the product

• To look at manufacturing changes to

decide if more tox is needed

Possible Use of Toxicogenomics, When Standardized

• To test multifunction combination

component particles vs the entire product

• To compare various sizes of nanosize

particles vs large sized particles

• To look at manufacturing changes

Considerations (a)

• Standard in vivo tests would generally

address the safety concerns

• Of more than 25 drug products that are

currently nanosize, no indication that standard analyses are inadequate to detect any different tissue distribution, retention, or toxicity

• However, need to follow closely as new

types of nanoparticle products are evaluated

Considerations (b)

• Work is needed to address the various

characterization issues, which affect the tox evaluation

• Work is needed to assess the utility of in vitro

assays in a number of areas

• Work is need to address some ADME issues
• Work is needed to assess the utility of omic

studies in a number of contexts