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Evaluation of Therapeutic Equivalence for the Follow-On Version of Intravenously Administered Non-Biological Complex Drugs

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Abstract

The interchangeability evaluation for generic drugs formulated as intravenous injections normally only requires assessments of pharmaceutical equivalence (PE) when the medicinal products are simple small-molecule drugs. However, intravenously administered non-biological complex drugs (NBCDs), such as liposomes, microsphere suspension, or fat emulsion, have inherent passive disposition selectivity due to their special formulations, thereby the in vivo drug performances are improved. Because of the complexity in formulation, the in vitro pharmaceutical investigations of follow-on NBCDs are more complicated than those required for generic small-molecule drugs. In addition to qualitative and quantitative sameness of the active and inactive ingredients, it is required to comparatively study the static and kinetic microscopic particle-related physiochemical properties of the follow-on NBCDs versus the reference products. Moreover, for complex formulations that have a significant impact on the biodistribution of the drug compound, an in vivo bioequivalence (BE) study is also important. Since NBCDs that demonstrated bioequivalence through the conventional BE approach have been found inequivalent in efficacy or safety to the reference products, pivotal BE studies for follow-on NBCDs are required to take both encapsulated/total drug and free drug as the analytes to address release kinetics and biodistribution of the active pharmacological ingredient in the body. This manuscript reviews the 26 U.S. FDA published product-specific guidelines for intravenous injections. In general, these NBCDs can be stratified into four groups according to their release kinetics and ability of bio-membrane penetration. Group 1 consists of seven small-molecule, non-complex drugs; group 2 included four NBCDs with either microscale particle size or rapid dissolution property; group 3 include five loosely packed NBCDs (fat emulsions) and one quickly released ophthalmic liposomal drug; and the last group contains four cytotoxic liposomal or protein-bound NBCDs and five iron carbohydrate complexes. The requirements of the corresponding guidelines range from simple proof of PE between the test and the reference products, to a collection of studies that demonstrate the key manufacturing process (e.g. liposome loading), the particle- or vehicle-wise static and kinetic physiological characterizations, the dissolution test, and BE evaluation of both total/encapsulated drug form and free drug form between the follow-on NBCDs and their reference products. Such studies are challenging in implementation. Therefore, a variety of alternative approaches are proposed in this article.

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Authors and Affiliations

  1. China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing, 100070, People’s Republic of China

    Zhuo Sun & Xia Chen

  2. Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China

    Zhuo Sun & Ji Jiang

  3. Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, People’s Republic of China

    Xia Chen

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  1. Zhuo Sun
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  2. Ji Jiang
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ZS performed the literature search and drafted the manuscript; JJ was responsible for manuscript review; and XC had the idea for the article, and drafted and critically revised the manuscript.

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Correspondence to Xia Chen.

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Funding

This study was supported by the National Grant for New Drug Development (2017ZX09304018) and Chinese National Natural Fund Grant (81671369).

Conflicts of interest

Zhuo Sun, Ji Jiang and Xia Chen declare they have no potential conflicts of interest that may be relevant to this manuscript.

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Sun, Z., Jiang, J. & Chen, X. Evaluation of Therapeutic Equivalence for the Follow-On Version of Intravenously Administered Non-Biological Complex Drugs. Clin Pharmacokinet 59, 995–1004 (2020). https://doi.org/10.1007/s40262-020-00889-9

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