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Measuring Exposure Levels of Drug Products Containing Nanomaterials
Katherine Tyner, Ph.D.
CDER/OPQ
US Food and Drug Administration
July 8, 2015
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Disclaimer
This talk reflects the views of the author and should not be construed to represent FDA’s views or policies The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services.
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Agenda
• Considerations for intentional exposure studies
• In vitro examples
• In vivo examples
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Agenda
• Considerations for intentional exposure studies
• In vitro examples
• In vivo examples
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An Intentional Discussion • In the majority of instances, the administration of drug products
containing nanomaterials means an intentional exposure – Unintentional exposure is possible and is part of a robust risk assessment
• Know the exposure has occurred
– Material – Dose – Pharmacokinetics/Toxicity (PK/TOX) – ADME (adsorption, distribution, metabolism, elimination)
• Detection is still key
– In vitro – In vivo models – Clinical
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Platform
Example Name NDA
Approval Indication
Liposome DOXIL® (Doxorubicin) 19951 Cancer
Inorganic nanoparticle FERRLECIT® (Sodium ferric gluconate complex) 19992 Anemia
Protein nanoparticle ABRAXANE® (Paclitaxel) 2005 Cancer
Polymer nanoparticle MACUGEN® (Pegaptanib sodium) 2004 Macular degeneration.
Emulsion RESTASIS® (Cyclosporine) 2002 To increase tear production
Lipid complex AMPHOTEC® (Amphotericin B) 1996 Invasive aspergillosis
Nanotube SOMATULINE DEPOT® (Lanreotide acetate) 2007 Acromegaly
Nanocrystal TRICOR® (Fenofibrate) 20043 Hypercholesterolemia
Micelle TAXOTERE®(Docetaxel) 1996 Cancer
1 First ANDA approval in 2013 2 First ANDA approval in 2011 3 First ANDA approval in 2011
Nanomaterials in Drug Products: CDER Examples
Tyner KT et al. WIRES Nanomedicine and Nanotechnology 2015.
Analytical Methods for Detecting Nanomaterials in Biological Systems • Non-carbon nanomaterials have methodology for
quantification and characterization • Detection of elemental signal & visual confirmation • Example: ICPMS, TEM/EDS
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?
Untreated animal
Analytical Methods for Detecting Nanomaterials in Biological Systems
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PK/ADME/Toxicity
• Pharmacokinetics (PK) is the study of the kinetics of absorption, distribution, metabolism and excretion of drugs and their pharmacologic, therapeutic or toxic response in animals and man
• ADME – Adsorption
• How it gets in the body – Distribution
• Where it goes in the body – Metabolism
• How the body breaks it down – Elimination
• How the body gets rid of it
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PK/ADME Methods & Nanomaterials
• Analytical methods – Most popular techniques for small molecules are radiolabeling and bioanalytical
techniques – Radiolabeling or fluorescently tagging nanomaterials may alter biodistribution
• Common bioanalytical techniques are not always valid for nanomaterials
– Example: Nanomaterials interacting with filtration step or chromatography columns
• Variety of matrices – Blood, urine, feces, on and off-target tissues
• Questions/considerations
– What is being measured/labeled (drug vs carrier)? – Does the nanomaterial remain intact?
• How are the constituents being identified – Is the bioanalytical method appropriate?
• Controls • Testing conditions
Before
After
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Detection and Quantitation of Nanomaterials in Biological Matrices
• HPLC-MS – Dendrimers, Polymers, Drugs, Metabolites, Fullerenes
• Capillary Electrophoresis
– Fullerenes
• Radiolabeling – Liposomes, Dendrimers, Polymers
• ICP-MS & Neutron Activation Analysis
– Metallic Nanoparticles (e.g., Gold) – Metal Oxides
• Electron Microscopy
– EDS, EELS (Detection and confirmation of composition)
• Optical Microscopy – Raman, Hyperspectral imaging (Detection)
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Serum
Serum + Dendrimer
Agenda
• Considerations for intentional exposure studies
• In vitro examples
• In vivo examples
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In Vitro Examples: Is the Method Appropriate? Controls
Hyperspectral Imaging Positive id
Naïve cells
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- Mass balance & control of exposure
- Cell culture conditions influence assay results
- Artificial constraints and/or parameters may influence results
Bancos S et al. J Nanobiotechnology 2015, 12
Static-based culture conditions Inserts-based culture conditions
Suspension-based culture conditions
In Vitro Examples: Is the Method Appropriate? Design Considerations
Agenda
• Considerations for intentional exposure studies
• In vitro examples
• In vivo examples
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In Vivo Examples
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0.0%0.5%1.0%1.5%2.0%2.5%3.0%3.5%
0 500 1000 1500
min
% ID
/mL
TNF-Au NP PK in rats, [TNF] by ELISA; [Au] by ICP-MS
Stern S.T. et. al. J. Control Release, 2010, 146, 164-174.
In Vivo Example: What is Being Measured? Complementary Analysis
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0123456789
0 5 10 15 20 25 30 35 40 45 50Time (hours)
% In
ject
ed d
ose
3 H /m
L
00.050.10.150.20.250.30.350.40.45
% In
ject
ed d
ose
14C
/mL3H-Liposome
14C-Ceramide
Vd (mL*kg-1)
Mean ± SD
Ceramide 1020 ± 478
Liposome 63 ± 19
In Vivo Example: Does the Nanomaterial Remain Intact? Dual Labeling
Zolnik, B.S. et. al. Drug Metab Dispos, 2008, 36, 1709-1715 18
In Vivo Example: Is the Method Appropriate? Capillary Electrophoresis
Chan, K.C.; Patri, A.K.; Veenstra, T.D.; McNeil, S.E.; Issaq, H.J.; Electrophoresis; 2007, 28, 1518-1524 19
0100200300400500600700800
urineday 1
fecesday 1
urineday 4
fecesday 4
mg/
kg S
i
SiO2 NPControl
- Detection - Limits of detection - Limits of quantification - Nanomaterial interference - Appropriate controls - Well-designed studies
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In Vivo Example: Is the Method Appropriate? Testing Considerations
Conclusions
• PK/ADME determination for drug products containing nanomaterials is an evolving area
• Techniques & methods exist to detect nanomaterials within biological tissues
– Multiple endpoints/methods
• Multiple issues and/or considerations may confound method development and analysis
– Appropriate controls – Well designed studies
• Regulatory science projects continue to address these issues
– Collaboration opportunities!
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Acknowledgements
• Dr. Anil Patri, Director, NCTR-ORA Nanotechnology Core Facility
• The Nanotechnology Characterization Laboratory
• The authors would like to acknowledge the FDA White Oak Nanotechnology Core Facility for instrument use, scientific and technical assistance
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