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

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Abstract

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.

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Fig. 1: Determinants of target site delivery and residence of NP.
Fig. 2: Effect of increasing NP diameter on target site exposure.
Fig. 3: Effects of changes in cell association/dissociation and internalization of NP on extracellular and intracellular target site exposure to NP.

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Abbreviations

ANDA:

Abbreviated New Drug Application

API:

Active pharmaceutical ingredient

AUC:

Area under concentration-time-curve

BE:

Bioequivalence

C max :

Maximum concentration

CQA:

Critical quality attribute

C-T:

Concentration-time

ECM:

Extracellular matrix

FDA:

US Food and Drug Administration

k on, k off, and k in :

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

NP:

Nanotechnology products

PC:

Protein corona

PK:

Pharmacokinetic

QSP:

Quantitative systems pharmacology

RES:

Reticuloendothelial system

RLD:

Reference listed drug.

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Funding

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.

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Authors and Affiliations

  1. Institute of Quantitative Systems Pharmacology, 1815 Aston Avenue, suite 107, Carlsbad, California, 92008, USA

    Jessie L.-S. Au, Ze Lu, Roberto A. Abbiati & M. Guillaume Wientjes

  2. Optimum Therapeutics LLC, Carlsbad, California, 92008, USA

    Jessie L.-S. Au, Ze Lu & M. Guillaume Wientjes

  3. Department of Pharmaceutical Sciences, University of Oklahoma, Oklahoma City, Oklahoma, 73117, USA

    Jessie L.-S. Au & Roberto A. Abbiati

  4. College of Pharmacy, Taipei Medical University, Taipei, Taiwan, Republic of China

    Jessie L.-S. Au

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  1. Jessie L.-S. Au
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Correspondence to Jessie L.-S. Au.

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

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Au, J.LS., Lu, Z., Abbiati, R.A. et al. Systemic Bioequivalence Is Unlikely to Equal Target Site Bioequivalence for Nanotechnology Oncologic Products. AAPS J 21, 24 (2019). https://doi.org/10.1208/s12248-019-0296-z

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