In Silico Methods for Development of Generic Drug–Device Combination Orally Inhaled Drug Products

Abstract

The development of generic, single‐entity, drug–device combination products for orally inhaled drug products is challenging in part because of the complex nature of device design characteristics and the difficulties associated with establishing bioequivalence for a locally acting drug product delivered to the site of action in the lung. This review examines in silico models that may be used to support the development of generic orally inhaled drug products and how model credibility may be assessed.

Predicting systemic and pulmonary tissue barrier concentration of orally inhaled drug products

“…It is possible that this enhanced precision will allow the PBPK model to simultaneously capture pulmonary and gastrointestinal tract absorptions with greater accuracy as discussed in a recent review of in silico methods for generic orally inhaled drug products. [13] In comparison, most other published studies have used simplified whole-lung dosimetry codes to predict particle deposition in the respiratory tract. [95, 96] The outcomes of these codes were used as inputs in further downstream modeling of drug pharmacokinetics.…”

“…potential differences in regional deposition was explored as shown in Table 5 and Fig 13 . However, regional absorption may be different than regional deposition if absorption is dissolution-or permeability-limited. Other potential limitations in our current framework are a lack of device specific effects (such as single actuation content and carrier effects for DPIs and plume geometry and spray pattern for MDIs), [13,104] a lack of other clearance mechanisms (such as drug phagocytosis by alveolar macrophages and cleared by transport to the lungdraining lymph nodes), [105,106] and lung region-specific involvement of metabolic and transported enzymes and proteins that may modulate the lung retention and bioavailability of some drugs. [107] Hence, overall it is possible that the lung tissue concentration of inhaled drugs may be overpredicted in absence of these modules in the model framework.…”

“…[2,3] Compared to oral or intravenous routes, the inhalation route offers several advantages, such as: i) promoting high local drug concentrations directly at the site of action in diseased lung tissue, which may not be achievable efficiently by other routes, [4] ii) avoiding ''first pass metabolism'' of the liver which Gastroplus™ (Simulations Plus Inc., Lancaster, CA, USA) which has mechanistic modules for regional deposition, dissolution, and permeation of inhaled drugs, [20] and SimCyp Simulator™ (Certara, Sheffield, United Kingdom) that has pulmonary delivery modules by reducing dissolution and epithelial permeation into a single first order process through a single pulmonary compartment. [For further information on available modeling approaches and their role in the development of OIDPs and devices, please refer to the reviews by Borghardt et al, [21] Backman et al, [22] and Walenga et al [13]] Nonetheless, although these previous modeling efforts and available tools have proven to be useful, assessment of lung-selectivity has so far proven to be elusive and questions remain.…”

Evaluation of Impulse Oscillometry in Respiratory Airway Casts with Varying Obstruction Phenotypes, Locations, and Complexities

“…It is anticipated that CFD modeling of IOS testing with a patient-specific airway geometry with a controlled lung function variation (i.e., before and after treatments) can provide correlations between the IOS endpoints and regional lung function [56]. To date, such correlations are still empirical, while quantitative correlations are not available [57]. The direct comparison between CFD simulations and IOS testing in the same patients with controlled lung function variations will hopefully shed new light on this less-explored area.…”

American Society for Clinical Pharmacology and Therapeutics 2019 Annual Meeting Pre‐Conferences

“…The PBPK‐related papers published in this special issue from the FDA reflect current practices and challenges in the field. Given the difficulties associated with establishing BE for orally inhaled drug products, the review examines the utility of different models in this space and discusses how model verification can be achieved. In general, challenges to verify PBPK models stand for locally acting drug products given that the drug concentrations at the site of action are not easily measurable and systemic concentrations may not reflect drug delivery at the site of action or are not detectable.…”