Inhaled biopharmaceutical drug development: nonclinical considerations and case studies

Abstract

Biopharmaceuticals are complex molecules often manufactured from living systems and their specificity and novelty holds great promise for the treatment of chronic diseases for which there are currently no cures. The inhalation route of biopharmaceutical drug delivery is attractive because the large surface area of the lung, and close proximity of the alveolar and vascular systems, maximizes the potential for drug delivery to the lung and/or systemic circulation. In addition, costs of delivery to the patient are potentially much reduced, in comparison with parental administration, since inhalation is non-invasive and likely to promote patient compliance. However, in comparison with small molecule drug development, developing an inhaled biopharmaceutical that is effective and safe for human use is associated with many challenges. This review considers some general principles of drug delivery to lung and issues associated with the translation of proof of concept studies to toxicology safety studies (e.g. aerosol generation, species selection, exaggerated pharmacology, and immunogenicity). This review also presents a summary of nonclinical and clinical data from inhaled biopharmaceuticals which are either marketed for human use or in Phase II clinical trials (e.g. DNase, insulin, human growth hormone, vaccines, therapeutic plasmid DNA complexes).

Insights on animal models to investigate inhalation therapy: Relevance for biotherapeutics

“…However, it is accepted practice to assess whether differences in the PK/PD profile of the biopharmaceutical between the first and last dose occur or whether there is evidence of immune-mediated toxicity in nonclinical studies. In such cases, ADA investigations may be warranted (McElroy et al, 2013).…”

“…Since the toxicity of many biopharmaceutics is often related to their mechanism of action, for example hypoglycaemia following insulin administration, the dose increases routinely used in toxicology studies may induce a toxic pharmacologic response, which may be independent of the intrinsic toxicology . For this reason, ICH S6 guidelines require pharmacodynamic endpoints in nonclinical toxicology study design (McElroy, 2013). In such cases, the intrinsic and biological toxicity can and should also be assessed in the pharmacological species of interest, as well as animal models of disease.…”

Dry powder inhalation: past, present and future

“…Again 20 years later, it has to be acknowledged that still more efficient aerosol devices are needed, that formulations have to be safer and bioavailability has to be improved [169]. McElroy et al compared the results for inhaled proteins from different studies, showing that systemic bioavailability for compounds with mol weights (MWs) <10 kDa can vary from almost 0% to 100%, whereas for MWs >10 kDa, 60% is maximal (so far) [170]. Therefore, bioavailabilities are often too low for cost-effective and reliable treatments [152].…”

Pulmonary Administration: Strengthening the Value of Therapeutic Proximity

“…In the case of nanomedicines, one of the main challenges arises from the fact that nanoparticles are extremely difficult to detect and quantify once distributed in an organism. Additionally, degradation or aggregation of the nanocarriers, interaction with biomolecules leading to alteration of the biological fate, and the process of drug release are extremely difficult to investigate using classical approaches (75,79).…”

“…One strategy complementary to classical approaches for the tracking and quantification of nanoparticle-based complexes consists of using labeled particles, which implies the creation and use of dedicated technology for, (1) the labeling, (2) the visualization at organ, tissue, cellular and/or subcellular level of particles and drug-nanoparticle complexes, and (3) the quantification of nanoparticle-drug complexes, empty nanoparticles, non-complexed therapeutic molecule and degradation products (79,80).…”