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Cited by 31Nanoparticle-Based Drug DeliveryDrug Solubulity and Delivery SystemsProtein Interaction Studies and Fluorescence Analysis

Distinguishing Pharmacokinetics of Marketed Nanomedicine Formulations Using a Stable Isotope Tracer Assay

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Skoczen, Sarah L., Snapp, Kelsie S., Crist, Rachael M., Kozak, Darby, Jiang, Xiaohui, Liu, Hao, Stern, Stephan T.·2020·ACS Pharmacology & Translational Science
DOI 10.1021/acsptsci.0c00011PMC PMC7296544
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Abstract

The pharmacokinetics of nanomedicines are complicated by the unique dispositional characteristics of the drug carrier. Most simplistically, the carrier could be a solubilizing platform that allows administration of a hydrophobic drug. Alternatively, the carrier could be stable and release the drug in a controlled manner, allowing for distribution of the carrier to influence distribution of the encapsulated drug. A third potential dispositional mechanism is carriers that are not stably complexed to the drug, but rather bind the drug in a dynamic equilibrium, similar to the binding of unbound drug to protein; since the nanocarrier has distributional and binding characteristics unlike plasma proteins, the equilibrium binding of drug to a nanocarrier can affect pharmacokinetics in unexpected ways, diverging from classical protein binding paradigms. The recently developed stable isotope tracer ultrafiltration assay (SITUA) for nanomedicine fractionation is uniquely suited for distinguishing and comparing these carrier/drug interactions. Here we present the the encapsulated, unencapsulated, and unbound drug fraction pharmacokinetic profiles in rats for marketed nanomedicines, representing examples of controlled release (doxorubicin liposomes, Doxil; and doxorubicin HCl liposome generic), equilibrium binding (paclitaxel cremophor micelle solution, Taxol generic), and solubilizing (paclitaxel albumin nanoparticle, Abraxane; and paclitaxel polylactic acid micelle, Genexol-PM) nanomedicine formulations. The utility of the SITUA method in differentiating these unique pharmacokinetic profiles and its potential for use in establishing generic nanomedicine bioequivalence are discussed.

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  • Bioequivalence analysis by two one-sided t-test revealed that Abraxane and Genexol PM were bioequivalent in total drug pharmacokinetic parameters.

    “Bioequivalence analysis by statistical analysis (two one-sided t-test) revealed that the Abraxane® and Genexol® PM formulations were bioequivalent in total drug PK parameters.”

    From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [247]

    The Results (page unavailable) say Abraxane and Genexol-PM had no significant differences in total-drug PK parameters in rats and describe their total-drug PK as equivalent. But the Statistics section (page unavailable) specifies Student’s t test or one-way ANOVA with Tukey’s posthoc test, not a two one-sided t-test. The paper also says the products lack bioequivalence testing, so its rat PK comparison does not establish bioequivalence by the claimed analysis. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

  • The study demonstrated that doxorubicin (DOXIL and Sun Pharma) and paclitaxel (Abraxane and Genexol PM) nanoformulations had comparable encapsulated, unencapsulated, and unbound pharmacokinetic parameters.

    “They demonstrated that both doxorubicin (DOXIL® and Sun Pharma’s formulation) and paclitaxel (Abraxane® and Samyang’s Genexol® PM) nanoformulations had comparable encapsulated/unencapsulated/unbound PK parameters.”

    From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [247]

    The Results (page not provided) describe the doxorubicin formulations’ encapsulated, unencapsulated, and unbound PK parameters as very similar, though some differed significantly. They also describe Abraxane and Genexol-PM’s unencapsulated and unbound parameters as very similar. The claim overreaches for encapsulated paclitaxel PK: encapsulated drug was not observed for Abraxane and was observed only at the earliest time point for Genexol-PM. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • For the Taxol formulation, Cremophor EL micelles bind in rapid equilibrium with unbound drug; this binding was observed as an increase in protein binding that correlated with formulation concentration and influenced paclitaxel pharmacokinetics by decreasing clearance and volume of distribution.

    “This was the case for the SITUA when it was applied to the Taxol formulation in which Cremophor EL micelles bind in rapid equilibrium with unbound drug; this Cremophor EL micelle binding was observed as an increase in protein binding that correlated with formulation concentration, and influenced paclitaxel PK by decreasing both clearance and volume of”

    From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [247]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • SITUA enables analysis of drug subpopulations derived from nanomedicines in systemic circulation in pharmacokinetic studies and can also be used clinically.

    “This approach enables the analysis of the aforementioned subpopulations of drugs derived from nanomedicines in the systemic circulation in PK studies and can also be used clinically [247].”

    From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [247]

  • In a recent study, SITUA was applied to analyze pharmacokinetic profiles of several clinically approved nanomedicines and their generic or nanosimilar formulations, some lacking bioequivalence testing.

    “In a recent study, the authors applied the SITUA method to analyze the PK profiles of several clinically approved nanomedicines and their generic or nanosimilar formulations, some of which lack bioequivalence testing.”

    From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [247]

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Cited by

Sorted by citations

Authors
Skoczen, S. L., Snapp, K. S., Crist, R. M., Kozak, D., Jiang, X., Liu, H., & Stern, S. T.
Affiliations
  • Leidos Biomedical Research Inc. (United States) (US)
  • United States Food and Drug Administration (US)
  • Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland 21702, United States
ORCID
Venue
ACS Pharmacology & Translational Science
Publisher
American Chemical Society (ACS)
Published
2020-03-13
Volume
3
Issue
3
Pages
547-558
ISSN
2575-9108 (ISSN-L)
DOI
10.1021/acsptsci.0c00011
PMC
PMC7296544
OpenAlex
W3012542984
Cited by
31
References
1
Citations by year
2026: 4 · 2025: 3 · 2024: 7 · 2023: 4 · 2022: 3 · 2021: 6 · 2020: 4
FWCI
1.11
Type
journal article
Language
en
Open access
Licence
Locations
  • ACS Pharmacology & Translational Science (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute (HHSN2612008000001E)
  • U.S. Food and Drug Administration (HHSN26100024, HHSN261201500003I)
Topics
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
Keywords
controlled release, binding equilibrium, drug solubilization, liposomal doxorubicin

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