Pulmonary Administration: Strengthening the Value of Therapeutic Proximity

Abstract

In recent years inhaled systems have shown momentum as patient-personalized therapies emerge. A significant improvement in terms of therapeutic efficacy and/or reduction adverse systemic effects is anticipated from their use owing these systems regional accumulation. Nevertheless, whatever safety and efficacy evidence required for inhaled formulations regulatory approval, it still poses an additional hurdle to gaining market access. In contrast with the formal intravenous medicines approval, the narrower adoption of pulmonary administration might rely on discrepancies in pre-clinical and clinical data provided by the marketing authorization holder to the regulatory authorities. Evidences of a diverse and inconsistent regulatory framework led to concerns over toxicity issues and respiratory safety. However, an overall trend to support general concepts of good practices exists. Current regulatory guidelines that supports PK/PD (pharmacokinetics/pharmacodynamic) assessment seeks attention threatening those inhaled formulations set to be approved in the coming years. A more complex scenario arises from the attempt of implementing nanomedicines for pulmonary administration. Cutting-edge image techniques could play a key role in supporting diverse stages of clinical development facilitating this pharmaceutics take off and speed to patients. The ongoing challenge in adapting conventional regulatory frameworks has proven to be tremendously difficult in an environment where market entry relies on multiple collections of evidence. This paper intention is to remind us that an acceptable pre-clinical toxicological program could emerge from, but not only, an accurate and robust data imaging collection. It is our conviction that if implemented, inhaled nanomedicines might have impact in multiple severe conditions, such as lung cancer, by fulfilling the opportunity for developing tailored treatments while solving dose-related toxicity issues; the most limiting threat in conventional lung cancer clinical management.

Keywords: imaging; inhaled nanomedicines; lung cancer; pre-clinical and clinical studies; pulmonary administration; selective targeting; toxicity.

Figure 1

MXT C1.1 was selected due to its mesenchymal phenotype and its ability to produce lung metastases in vivo. Orthotopic implantation of cells (1 × 10⁶ cells) in the mammary fat pad of female BALB/c mice (Harlan Iberica, Barcelona, SP) was used to develop the primary tumor. Dissemination in distant organs, such as the pulmonary region was confirmed by histomorphology of the animal's lungs at the study endpoint (42 days). Animals were divided according to the inhaled formulation (randomized groups, n = 10): untreated control (group 1), plain SLN (group 2), paclitaxel-lipid nanoparticles (group 3). Each group received 6 administrations as depicted at the photo A mean tumor volume of 0.5 mm² in the control group was considered the study “end point.” The primary tumors volumes were measured using a Vernier caliper. The results were expressed as the following: the prevalence of detected lung metastasis, as well as number and volume. The correlation between lung metastasis invasion with the paclitaxel-lipid nanoparticles inhalation was evaluated by regression analysis. P-values <0.05 were considered statistically significant.

Figure 2

Representative workflow of the use of nuclear imaging to gain information related to the distribution of NCs after intratracheal insufflation. Gallium-67 labeled LPs (A) are administered to healthy rats. (B) In vivo (C) or Ex vivo (E) images can be obtained using SPECT. In vivo imaging enables quantification of the regional distribution. (D) Ex vivo autoradiography studies provide information about distribution at a higher spatial resolution (F) bottom. A photograph of the tissue slice is also shown (F) top. In the case shown, liposomes (LPs, as a model of nanocarrier) were labeled with Gallium-67 (gamma emitter, T1/2 = 3.3 days, E_max = 93, 184, and 296 keV) using a trans chelation method. The LPs were administered to healthy rats using the Penn-Century insufflators, and In vivo images were acquired using SPECT, enabling the determination of the regional distribution of the NCs within the lungs by drawing volumes of interest in the different lung lobes. In parallel studies, the lungs were harvested after appropriate tissue fixation and imaged using SPECT, resulting in more detailed images due to suppression of lung motion. Finally, autoradiography studies on tissue slices provided information about distribution at a higher spatial resolution.

Figure 3

Different paths of regulatory requirements are summarized in the schematic diagram. Investigational new drug applications (IND), using existing or innovative nanoparticle formulations, will benefit from images supporting safety and efficacy evidence to complete “non-image” conventional end-points, pre-clinically and clinically, including quality and efficacy proof of concept, PK/PD, sub-acute to chronic toxicity, repeated dose toxicity, genotoxicity, carcinogenicity, reproductive toxicity, etc. Functional medical images of non-invasive lung administration either for inhaled active molecules or image agents can strengths the approval decision-make process. Bearing this in mind, regulatory acceptance of imaging-based evidence might have a time reduction impact in the benefit-risk assessment whenever image-guided “drug” delivery provides clinically significant data. Owing its potential to cover “drug” biodistribution cycle including body response and tissue alterations, and knowing that most of the new targetable cell events are common in cancer growth and survival, it is expectable that innovative molecules, targeting newly identified cell function alterations/abnormal signaling cascades, might have the decision-make process abbreviated even for broader indications.