Drug Delivery
where the pharmacological activity of the test material may be evaluated and any change in potency following aerolisation noted, in addition to the use of a binding assay. Since such assays tend to be product-specific, early dialogue with the selected CRO is encouraged to ensure smooth tran- sition from exploratory studies to regulatory GLP safety assessment.
Depending on the composition of the formulation, the ratio of gravimetric and chemical analysis for most biopharmaceutical powders remains consistent with the original formulation composition due to the type of formulation preparation technique. The principle reason for a disparity is in case two different particle sizes are used in the prepara- tion with powder formulations and for suspension with liquid formulations.
Bioanalytical and biomarker considerations in pre-clinical research Non-clinical safety studies with biopharmaceuti- cals intended for inhaled delivery have a number of additional considerations that are unique to this method of administration. Although confirmation of drug exposure by comprehensive pharmacoki- netic/toxicokinetic (PK/TK) evaluation is expected in all biopharmaceutical safety assessment pack- ages, it is important to consider that for inhaled biopharmaceutical products, systemic exposure may not always be achievable or indeed desirable. For instance, there may be limited transport of the delivered biopharmaceutical due to its size (molecules larger than 50kDa display reduced bioavailability) or targeted delivery and binding to a receptor in the lung or a specific cell population may lead to retention of the drug in the lung. Therefore, sampling of the local environment by bronchoalveolar lavage (BAL) to confirm that the intended delivery has been achieved, as well as establishing systemic exposure, should be consid- ered. The feasibility of obtaining BAL measure- ments requires careful consideration as although possible, in-life sampling carries an inherent risk to the animal. For this reason, strict sampling limits are imposed and it is highly likely that a full-lung TK profile will not be possible in non-rodent species, with rodent studies requiring additional animals for such assessments. The analytical approaches required for TK assessment of biophar- maceuticals may differ to those more commonly employed for NCEs, with immunoassays based on ligand binding assessment often required, although LC-MS/MS-based assays can still be utilised if a signature peptide has been identified or for smaller products such as oligonucleotides.
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As mentioned earlier in this article, the safety profile of a biopharmaceutical in pre-clinical stud- ies can only be adequately assessed in a pharmaco- logically-relevant species, ideally where the intend- ed clinical biology can be replicated. As a result, it is imperative that markers to confirm PD activity are included in safety assessment studies wherever possible. Appropriate markers should be identified based on the expected pharmacological effect and assessment performed at timepoints relevant to its induction. A detailed understanding of the intend- ed biology is therefore required and this should include any downstream effects in addition to the direct effect of the drug interacting with its target. The relationship of this biology in the non-clinical species to the clinical situation should also be thor- oughly investigated so that any differences in the level or distribution of the target expression can be properly understood and interpreted. In addition to PD end-points, safety biomarkers can also be incorporated into the non-clinical safety studies. These can include markers of immune acti- vation (CRP, cytokines, immune cell activation and/or mobilisation), immunogenicity assessment (discussed later), as well as assessment of ‘off-target’ pathways that have been identified for certain class- es of drugs. For example, prolonged coagulation and complement activation have long been associat- ed with oligonucleotides, especially those with phos- phorothioate backbone or products with lipid-based formulations. The exact parameters required for analysis are selected based on the biology and the risk specific to an individual product, and if this risk is unknown or theoretical it can be assessed in pre- liminary studies to determine whether further fol- low-up in pivotal studies is required.
Immunogenicity
One of the considerations specific to biopharma- ceuticals in R&D is the development of immuno- genicity. Administration of any human protein to an animal species is essentially delivery of a non- self material to some degree and development of an immune response specific to the drug can be induced following delivery by any of the main routes of administration. The lung is predisposed to remove foreign material and populations of the immune system, such as macrophages, are specifi- cally-designed to support this, so the potential for immunogenicity responses should be explored, whether intended biology or not. Although it is accepted that immunogenicity in an animal model in pre-clinical studies is not predictive of immuno- genicity in the clinical setting, the recognised con- sequences of immunogenicity warrant at least the
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