Systemic Bioequivalence Is Unlikely to Equal Target Site Bioequivalence for Nanotechnology Oncologic Products
- 50 Downloads
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.
KEY WORDSFDA nanotechnology quantitative systems pharmacology systemic bioequivalence target site bioequivalence
Abbreviated New Drug Application
Active pharmaceutical ingredient
Area under concentration-time-curve
Critical quality attribute
US Food and Drug Administration
- kon, koff, and kin
Respective rate constants of NP binding and release from cell membrane, and internalization
Quantitative systems pharmacology
Reference listed drug.
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.
- 2.Sorger PK, Allerheiligen SRB, Abernethy DR, Altman RB, Brouwer KLR, Califano A, et al. Quantitative and systems pharmacology in the post-genomic era: new approaches to discovering drugs and understanding therapeutic mechanisms. An NIH White Paper by the QSP Workshop. Group. 2011.Google Scholar
- 3.Lionberger R. Using quantitative methods and modeling to transform generic drug development and review. https://www.fda.gov/downloads/Drugs/NewsEvents/UCM582148.pdf. 2017. Accessed 31 Oct 2018.
- 4.USFDA. Guidance for industry: considering whether an FDA-regulated product involves the application of nanotechnology. https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM401695.pdf. 2014. Accessed 31 Oct 2018.
- 5.USFDA. Guidance for industry: drug products, including biological products, that contain nanomaterials. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM588857.pdf. 2017. Accessed 31 Oct 2018.
- 9.USFDA. Drugs@FDA database. https://www.fda.gov/Drugs/InformationOnDrugs/ucm135821.htm 2018. Accessed 10 Dec 2018.
- 13.USFDA. Generic drugs: questions & answers. https://www.fda.gov/drugs/resourcesforyou/consumers/questionsanswers/ucm100100.htm. 2018. Accessed 31 Oct 2018.
- 14.Code of Federal Regulations. Applications for FDA approval to market a new drug - definations, 21 CFR 314.3. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.3. 2018. Accessed 31 Oct 2018.
- 15.Code of Federal Regulations. Types of evidence to measure bioavailability or establish bioequivalence, 21 CFR 320.24. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=320.24. 2018. Accessed 31 Oct 2018.
- 16.USFDA. Guidance for industry: submission of summary bioequivalence data for ANDAs. https://www.fda.gov/downloads/Drugs/.../Guidances/UCM134846.pdf. 2011. Accessed 31 Oct 2018.
- 17.USFDA. Guidance for industry: bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an ANDA. https://www.fda.gov/downloads/drugs/guidances/ucm377465.pdf. 2013. Accessed 31 Oct 2018.
- 18.USFDA. Guidance for industry: statistical approaches to establishing bioequivalence. https://www.fda.gov/downloads/drugs/guidances/ucm070244.pdf. 2001. Accessed 31 Oct 2018.
- 19.USFDA. Reducing the hurdles for complex generic drug development. https://www.fda.gov/NewsEvents/Newsroom/FDAVoices/ucm612010.htm. 2017. Accessed 31 Oct 2018.
- 20.USFDA. Guidance for Industry: formal meetings between FDA and ANDA applicants of complex products under GDUFA. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm578366.pdf. 2017. Accessed 31 Oct 2018.
- 21.USFDA. Guidance for industry: use of nanomaterials in food for animals. https://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM401508.pdf. 2015. Accessed 31 Oct 2018.
- 22.USFDA. Guidance for industry: assessing the effects of significant manufacturing process changes, including emerging technologies, on the safety and regulatory status of food ingredients and food contact substances, including food ingredients that are color additives. https://www.fda.gov/downloads/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/UCM616225.pdf. 2014. Accessed 31 Oct 2018.
- 23.USFDA. Guidance for industry: safety of nanomatrials in comestic products. https://www.fda.gov/downloads/Cosmetics/GuidanceRegulation/GuidanceDocuments/UCM300932.pdf. 2014. Accessed 31 Oct 2018.
- 24.USFDA. Guidance for industry: liposome drug products chemistry, manufacturing, and controls; human pharmacokinetics and bioavailability; and labeling documentation. https://www.fda.gov/downloads/drugs/guidances/ucm070570.pdf . 2018. Accessed 31 Oct 2018.
- 25.USFDA. Orange Book preface. https://www.fda.gov/drugs/developmentapprovalprocess/ucm079068.htm. 2018. Accessed 31 Oct 2018.
- 32.Lu Z, Wientjes MG, Au JL. Development of drug-loaded particles for intraperitoneal therapy. In: Wim P. Ceelen, Edward Levine, editors. Intraperitoneal cancer therapy: principles and practice. CRC Press; 2015. p. 331–344.Google Scholar
- 36.Au JL, Abbiati RA, Wientjes MG, Lu Z. Target site delivery and residence of nano-medicines: application of quantitative systems pharmacology. Pharmacol.Rev. (Accepted).Google Scholar
- 48.Mariam J, Sivakami S, Dongre PM. Albumin corona on nanoparticles - a strategic approach in drug delivery. Drug Deliv. 2015:1–9.Google Scholar
- 50.Bonvin D, Aschauer U, Alexander DTL, Chiappe D, Moniatte M, Hofmann H, et al. Protein corona: impact of lymph versus blood in a complex in vitro environment. Small. 2017;13.Google Scholar
- 67.Abbiati RA, Au JL. Quantitative systems pharmacology on cancer drug delivery to target sites: application of chemical engineering tools. In: Manca D, editor. Quantitative systems pharmacology: models and model-based systems with applications. Elsevier; 2018. p. 239–270.Google Scholar
- 70.Nitta N, Takakusagi Y, Kokuryo D, Shibata S, Tomita A, Higashi T, et al. Intratumoral evaluation of 3D microvasculature and nanoparticle distribution using a gadolinium-dendron modified nano-liposomal contrast agent with magnetic resonance micro-imaging. Nanomedicine. 2018;14:1315–24.CrossRefGoogle Scholar
- 82.Reed RK, Townsley MI, Taylor AE. Estimation of capillary reflection coefficients and unique PS products in dog paw. Am J Phys. 1989;257:H1037–41.Google Scholar
- 85.Celgene Corporation and Abraxis BioScience LLC Citizen Petition. https://www.regulations.gov/contentStreamer?documentId=FDA-2015-P-0732- 0001&attachmentNumber=1&contentType=pdf. 2015. Accessed 31 Oct 2018.
- 86.Desai, N. P., Soon-Shiong, P., and Trieu, V. Compositions and methods of delivery of pharmacological agents. U.S. Patent 7,820,788. 2010.Google Scholar
- 87.Desai, N. P., Soon-Shiong, P., and Trieu, V. Compositions and methods of delivery of pharmacological agents. U.S. Patent 8,138,229. 2012.Google Scholar
- 88.Desai, N. P. and Soon-Shiong, P. Formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof. U.S. Patent 8,853,260. 2014.Google Scholar
- 89.Abraxane® Package Insert. https://media.celgene.com/content/uploads/abraxane-pi.pdf 2018. Accessed 31 Oct 2018.