In Vitro and In Vivo Equivalence Testing of Nanoparticulate Intravenous Formulations

Abstract

The topic of bioequivalence evaluation of nanoparticulate intravenous formulations is one that has been intensely debated in recent times since the release of the specific recommendations by many regulatory authorities worldwide. Product specific bioequivalence guidelines for many of the nanoparticulate systems where therapeutic molecules are directly coupled (human albumin bound paclitaxel nanosuspension), functionalized (iron- carbohydrate preparations) or entrapped/coated to a carrier (doxorubicin liposomal formulations), have been approved by the drug regulatory agencies. These current regulatory procedures include complete characterization of the generic formulation in terms of its physicochemical characteristics, pharmacokinetics disposition and/or non clinical testing with respect to the reference formulation. The concept of in vitro equivalency is emerging as a valuable tool in these guidances as generic product differing in in vitro parameters can result in a different biopharmaceutical profile with respect to pharmacokinetics and biodistribution. Furthermore, in case of systems with entrapped drug, classical pharmacokinetic parameters alone may only ensure the equivalent clearance of test and reference product from systemic circulation but may fail to detect the extent to which the nanoparticles are taken up by different target organs and, consequently, the safety and efficacy effects. Hence, additional tissue distribution study in preclinical study models has reflected in recent guidances. Understanding and interpretation of these regulatory requirements thus presents most critical component of a generic product development cycle. This article reviews these current regulatory procedures with special emphasis on in vitro population bioequivalence (POP BE) and preclinical testing of generic formulations.

Key words

population bioequivalence - intravenous - non clinical - liposomes - in vitro

• References

• 1 US Department of Health and Human Services, Public Health Services – Food and Drug Administration “From test tube to patient: Improving health through human drugs 1999 Available at: http://www.fda.gov/Drugs/EmergencyPreparedness/BioterrorismandDrugPreparedness/ucm134444.htm Accessed on 5 September 2012
• 2 US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) 2011 Draft Guidance on Paclitaxel 2012 Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM320015.pdf Accessed on 3 October 2012
• 3 US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) 2011 Draft guidance on Doxorubicin hydrochloride 2010 Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM199635.pdf Accessed on 3 October 2012
• 4 European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP) Assessment report doxorubicin SUN July 2011 EMEA/H/C/002049. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/human/002049/WC500112957.pdf Accessed on 15 September 2012
• 5 US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) 2011 Draft guidance on iron sucrose 2012 Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM297630.pdf Accessed on 3 October 2012
• 6 European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Reflection paper on non-clinical studies for generic nanoparticle iron medicinal product applications. 2011 EMA/CHMP/SWP/100094/2011. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/04/WC500105048.pdf Accessed on 7 September 2012
• 7 US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) 2011 Draft Guidance on Azacitidine 2012 Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm082801.pdf Accessed on 3 October 2012
• 8 US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) 2011 Draft Guidance on Budesonide 2012 Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM319977.pdf Accessed on 3 October 2012
• 9 US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) Statistical information for in vitro bioequivalence 1999 Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070118.pdf Accessed on 5 September 2012
• 10 European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Reflection paper on the data requirements for intravenous liposomal products developed with reference to an innovator liposomal product. 2011 EMA/CHMP/SWP/806058/2009. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/07/WC500109479.pdf Accessed on 10 September 2012
• 11 US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) Guidance for industry. statistical approaches to establishing bioequivalence 2001 Available at: http://www.fda.gov/downloads/Drugs/…/Guidances/ucm070244.pdf Accessed on 5 September 2012
• 12 European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP) Guideline on the investigation of bioequivalence 2010 CPMP/EWP/QWP/1401/98. Available at http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf Accessed on 5 September 2012
• 13 Midha KK, McKay G. Bioequivalence; its history, practice, and future. AAPS J 2009; 11: 664-670
• 14 Chow SC, Shao J, Wang H. In vitro bioequivalence testing. Stat Med 2003; 22: 55-68
• 15 Christopher D, Adams W, Amann A et al. Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols. Part 3. Final report on a statistical procedure for determining equivalence. AAPS PharmSciTech 2007; 8: E90
• 16 Li BV, Ren K. A Step-wise Procedure for population bioequivalence (PBE) Analysis of orally inhaled and nasal drug product (OINDP) bioequivalence studies. GPhA/FDA 2011 Fall Technical Conference Bethesda 2011. Available at: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM292545.pdf Accessed on 5 September 2012
• 17 Li B, Christopher D, Dalby R. In Vitro Approaches to demonstrating bioequivalence-summary of discussions. PQRI Workshop on addressing the role of pharmacokinetics in establishing Bioequivalence for Orally Inhaled Drug Products. PQRI Conference Bethesda 2011. Available at: http://www.pqri.org/workshops/Bioequiv/imagespdfs/final/Session_1.pdf Accessed on 5 September 2012
• 18 Wang H, Zhang Y, Shao J et al. In Vitro bioequivalence testing. In: Encyclopedia of biopharmaceutical statistics. New York: Marcel Dekker Inc; 2003: 449-455
• 19 Blume HH. BE assessment of parenteral MR preparations: determination of free vs. encapsulated compound?. EUFEPS BA/BE Network Conference on MR products Barcelona, 23-24, 2011. Available at http://www.eufeps.org/files/Blume_H.pdf Accessed on 10 September 2012
• 20 Schellekens H, Klinger E, Muhlebach S et al. The therapeutic equivalence of complex drugs. Regul Toxicol Pharmacol 2011; 59: 176-183
• 21 Nakai K, Fujita M, Ogata H. New bioequivalence studies: individual bioequivalence and population bioequivalence. Yakugaku Zasshi 2000; 120: 1201-1208
• 22 Hauck WW, Anderson S. Types of bioequivalence and related statistical considerations. Int J Clin Pharmacol Ther Toxicol 1992; 30: 181-187
• 23 Anderson S, Hauck WW. Consideration of individual bioequivalence. J Pharmacokinet Biopharm 1990; 18: 259-273
• 24 Tothfalusi L, Endrenyi L. Limits for the scaled average bioequivalence of highly variable drugs and drug products. Pharm Res 2003; 20: 382-389
• 25 Tothfalusi L, Endrenyi L, Midha KK. Scaling or wider bioequivalence limits for highly variable drugs and for the special case of C (max). Int J Clin Pharmacol Ther 2003; 41: 217-225
• 26 Weiner BB. What is a Continuous Particle Size Distribution?. Brookhaven Instruments Corporation White Paper, USA 2011: 1-3
• 27 Horiba Scientific. A guidebook to particle size analysis. California- Horiba Instruments, Inc, USA 2012: 1-32
• 28 Kudasheva DS, Lai J, Ulman A et al. Structure of carbohydrate-bound polynuclear iron oxyhydroxide nanoparticles in parenteral formulations. J Inorg Biochem 2004; 98: 1757-1769
• 29 Dunn LL, Suryo Rahmanto Y, Richardson DR. Iron uptake and metabolism in the new millennium. Trends Cell Biol 2007; 17: 93-100
• 30 Danielson BG, Salmonson T, Derendorf H et al. Pharmacokinetics of iron(III)-hydroxide sucrose complex after a single intravenous dose in healthy volunteers. Arzneimittelforschung 1996; 46: 615-621
• 31 United States Pharmacopeial Convention . Iron Sucrose Injection, Official monograph in: The United States Pharmacopeia. United States Pharmacopeial Convention: Rockville 2008; 31: 2449-2451
• 32 Brissot P, Ropert M, Le Lan C et al. Non-transferrin bound iron: a key role in iron overload and iron toxicity. Biochim Biophys Acta 2012; 1820: 403-410
• 33 Martin-Malo A, Merino A, Carracedo J et al. Effects of intravenous iron on mononuclear cells during the haemodialysis session. Nephrol Dial Transplant 2012; 27: 2465-2471
• 34 Van Wyck D, Anderson J, Johnson K. Labile iron in parenteral iron formulations: a quantitative and comparative study. Nephrol Dial Transplant 2004; 19: 561-565
• 35 Van Wyck DB. Labile iron: manifestations and clinical implications. J Am Soc Nephrol 2004; 15: S107-S111
• 36 Wysowski DK, Swartz L, Borders-Hemphill BV et al. Use of parenteral iron products and serious anaphylactic-type reactions. Am J Hematol 2010; 85: 650-654
• 37 Meier T, Schropp P, Pater C et al. Physicochemical and toxicological characterization of a new generic iron sucrose preparation. Arzneimittelforschung 2011; 61: 112-119
• 38 Toblli JE, Cao G, Oliveri L et al. Comparison of oxidative stress and inflammation induced by different intravenous iron sucrose similar preparations in a rat model. Inflamm Allergy Drug Targets 2012; 11: 66-78
• 39 Toblli JE, Cao G, Oliveri L et al. Evaluation of toxicity and oxidative stress induced by intravenous iron isomaltoside 1000 in a nonclinical model. Arzneimittelforschung 2011; 61: 553-565
• 40 Toblli JE, Cao G, Oliveri L et al. Differences between original intravenous iron sucrose and iron sucrose similar preparations. Arzneimittelforschung 2009; 59: 176-190
• 41 Borchard G, Fluhmann B, Muhlebach S. Nanoparticle iron medicinal products – Requirements for approval of intended copies of non-biological complex drugs (NBCD) and the importance of clinical comparative studies. Regul Toxicol Pharmacol 2012; 64: 324-328
• 42 Rottembourg J, Kadri A, Leonard E et al. Do two intravenous iron sucrose preparations have the same efficacy?. Nephrol Dial Transplant 2011; 26: 3262-3267
• 43 Stein J, Dignass A, Chow KU. Clinical case reports raise doubts about the therapeutic equivalence of an iron sucrose similar preparation compared with iron sucrose originator. Curr Med Res Opin 2012; 28: 241-243