The AAPS Journal

, 21:24 | Cite as

Systemic Bioequivalence Is Unlikely to Equal Target Site Bioequivalence for Nanotechnology Oncologic Products

  • Jessie L.-S. AuEmail author
  • Ze Lu
  • Roberto A. Abbiati
  • M. Guillaume Wientjes


Approval of generic drugs by the US Food and Drug Administration (FDA) requires the product to be pharmaceutically equivalent to the reference listed drug (RLD) and demonstrate bioequivalence (BE) in effectiveness when administered to patients under the conditions in the RLD product labeling. Effectiveness is determined by drug exposure at the target sites. However, since such measurement is usually unavailable, systemic exposure is assumed to equal target site exposure and systemic BE to equal target site BE. This assumption, while it often applies to small molecule drug products that are readily dissolved in biological fluids and systemically absorbed, is unlikely to apply to nanotechnology products (NP) that exist as heterogeneous systems and are subjected to dimension- and material-dependent changes. This commentary provides an overview of the intersecting and spatial-dependent processes and variables governing the delivery and residence of oncologic NP in solid tumors. In order to provide a quantitative perspective of the collective effects of these processes, we used quantitative systems pharmacology (QSP) multi-scale modeling to capture the physicochemical and biological events on several scales (whole-body, organ/suborgan, cell/subcellular, spatial locations, time). QSP is an emerging field that entails using modeling and computation to facilitate drug development; an analogous approach (i.e., model-informed drug development) is advocated by to FDA. The QSP model-based simulations illustrated that small changes in NP attributes (e.g., size variations during manufacturing, interactions with proteins in biological milieu) could lead to disproportionately large differences in target site exposure, rending systemic BE unlikely to equal target site BE.


FDA nanotechnology  quantitative systems pharmacology systemic bioequivalence target site bioequivalence 



Abbreviated New Drug Application


Active pharmaceutical ingredient


Area under concentration-time-curve




Maximum concentration


Critical quality attribute




Extracellular matrix


US Food and Drug Administration

kon, koff, and kin

Respective rate constants of NP binding and release from cell membrane, and internalization


Nanotechnology products


Protein corona




Quantitative systems pharmacology


Reticuloendothelial system


Reference listed drug.


Funding Information

This work was supported in part by research grants R01GM100487 from the National Institute of General Medical Sciences and R01EB015253 from the National Institute of Biomedical Imaging and Bioengineering, NIH, DHHS, the Mosier Endowed Chair in Pharmaceutical Sciences at University of Oklahoma Health Sciences Center, and the Chair in Systems Pharmacology at Taipei Medical University.

Compliance with Ethical Standards

Conflict of Interest

JA, GW and ZL have ownership interests in Optimum Therapeutics LLC, which is involved in developing cancer nanotechnologies.


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Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Jessie L.-S. Au
    • 1
    • 2
    • 3
    • 4
    Email author
  • Ze Lu
    • 1
    • 2
  • Roberto A. Abbiati
    • 1
    • 3
  • M. Guillaume Wientjes
    • 1
    • 2
  1. 1.Institute of Quantitative Systems PharmacologyCarlsbadUSA
  2. 2.Optimum Therapeutics LLCCarlsbadUSA
  3. 3.Department of Pharmaceutical SciencesUniversity of OklahomaOklahoma CityUSA
  4. 4.College of PharmacyTaipei Medical UniversityTaipeiRepublic of China

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