Nanosize: What Can We Learn about Nonclinical Evaluations? Abby Jacobs CDER/FDA 1/2014 NOT official CDER/FDA policy

Transcription

1 Nanosize: What Can We Learn about Nonclinical Evaluations? Abby Jacobs CDER/FDA 1/2014 NOT official CDER/FDA policy

2 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?

3 The Interplay Between Characterization and Toxicology (b) How should the dose in a nonclinical study be described? Not only mg/kg or mg/m 2 Surface properties Protein binding properties Since there is always a particle size distribution, to what particle size range should we attribute various biologic effects?

4 Particle Properties (a) Changes in which properties could affect biologic properties? Slight differences in physical properties could impact tox

5 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

6 Inhalation Route-specific Issues (a) Local/respiratory toxicity Distribution in respiratory tissues Systemic bioavailability SC Sensitization

7 Dermal Route-specific Issues (b) Dermal and systemic bioavailability Increased hair follicle penetration Distribution to local lymph nodes Different effects in sunlight (TiO 2 and ZnO sunscreens)

8 IV Route-specific Issues (c) Liposome may have different tissue distribution and longer half-life of API Hemocompatability Sterility Ocular Intravitreal retention

9 Oral Route-specific Issues (d) 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

10 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?

11 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?

12 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 of previously tested and marketed products? ADME and a tox bridging study?

13 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

14 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?

15 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)

16 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

17 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

18 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

19 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