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FY2015 Regulatory Science Research Report: Nanotechnology: Nano Drug Products: Clinical Pharmacology and In Vivo Correlation

FY2015 Regulatory Science Research Report: Nanotechnology: Nano Drug Products: Clinical Pharmacology and In Vivo Correlation

Introduction

Nano drug products, such as liposomal drug products, protein-drug complex, and iron colloids, pose challenges in generic evaluation because the drug release and distribution may be significantly different from that of a conventional formulation without nano scale materials.  For example, doxorubicin hydrochloride liposome injection has a more favorable safety profile than doxorubicin injection because the nano scaled size of actively loaded liposome results in preferential accumulation at the target tumor site and reduced exposure at the other parts of the body.  A better characterization of these clinical pharmacology properties will help developing guidance to evaluate relative bioavailability between a generic formulation and its reference product.

Research

ORS uses two approaches to quantitatively characterize clinical pharmacology properties of nano drug products: to develop pharmacokinetic/pharmacodynamic models using population based modeling technique or mechanism based modeling technique, and to explore in vitro in vivo correlation in the process of developing compendial or bio-relevant in vitro drug release assays.  ORS has established collaboration with OTS and external experts through the grant or contract mechanism to conduct in vivo studies of nano drug products, evaluate their distribution properties, and develop in vitro drug release assays which may be predictive of in vivo performance. 

Figure 29. Rate constant vs. pH for doxorubicin uptake into blank liposomes containing 250 mM (NH4)2SO4 in liposome suspensions containing 3 mg/mL lipid at 37℃

Figure 29. Rate constant vs. pH for doxorubicin uptake into blank liposomes containing 250 mM (NH4)2SO4 in liposome suspensions containing 3 mg/mL lipid at 37℃

* J Pharm Sci. 2015 Mar;104(3):1087-98. doi: 10.1002/jps.24307. (FDA-sponsored project)

 

ORS staff facilitating research in this area

  • Dajun Sun, Lanyan (Lucy) Fang, Hong Wen, Xinyuan Zhang, and other ORS staff

Projects and Collaborators

  • Evaluation of Dissolution Methods for Complex Parenteral Liposomal Formulations
    • Site PI: Bradley Anderson (University of Kentucky)
    • Grant/Contract #: 1 U01 FD004892-01
  • Development of a Liposome Doxorubicin Product Drug Release Assay
    • Site PI: Peter Working (ZoneOne Pharma, Inc.)
    • Grant/Contract #: 1 U01 FD004893-01
  • An in vitro-in vivo correlation model to predict serum non-transferrin bound iron
    • Site PI: Amy Barton Pai (Albany College of Pharmacy and Health Sciences)
    • Grant/Contract #: 1 U01 FD004889-01
  • Evaluation of In Vitro Release Methods for Liposomal Amphotericin B
    • Site PI: Peter Working (ZoneOne Pharma, Inc.)
    • Grant/Contract #: 1 U01 FD005249-01
  • Evaluation of Iron Species in Healthy Subjects Treated with Generic and Reference Sodium Ferric Gluconate
    • Site PI: Sarah Michel (University of Maryland)
    • Grant/Contract #: 1 U01 FD005266-01
  • Internal Project: Determining the biodistribution of colloidal iron products in rats
    • FDA Collaborators: Rodney Rouse and Vikram Patel
    • FDA Center/Office/Division: FDA/CDER/OTS/OCP/DARS

Publications and Presentations

  • Fugit KD et al. Mechanistic model and analysis of doxorubicin release from liposomal formulations. J Control Release. 2015 Aug 23;217:82-91.
  • Csuhai E et al. Determination of key parameters for a mechanism-based model to predict doxorubicin release from actively loaded liposomes. J Pharm Sci. 2015 Mar;104(3):1087-98.
  • Yuan W et al. Development of flow-through USP 4 apparatus release assay for doxorubicin liposomes. American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Symposium (2014)
  • Dai Z et al. Development of a liposomal doxorubicin product drug release assay. AAPS Annual Meeting and Symposium (2014)
  • Pai AB et al. Performance of redox active and chelatable iron assays to determine labile iron concentrations from intravenous iron formulations. Innovation@CDER (2014)
  • Choi D et al. Kinetics and Equilibria Impacting the Liposomal Transport of Doxorubicin and the Development of a Mechanistic Model for Liposomal Drug Release. Innovation@CDER (2014)
  • Tang J et al. Development of the Liposomal Amphotericin B Release Assay. The National Institute for Pharmaceutical Technology and Education (NIPTE) conference, Rockville MD (April 30 – May 1, 2015)

Outcomes

  • Revision of Product-Specific Recommendation on Iron Sucrose Injection
  • Revision of Product-Specific Recommendation on Doxorubicin HCl liposome Injection

 

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