Biological Obstacles for Identifying In Vitro-In Vivo Correlations of Orally Inhaled Formulations

Abstract

Oral inhalation of drugs is the classic therapy of obstructive lung diseases. In contrast to the oral route, the link between in vitro and in vivo findings is less well defined and predictive models and parameters for in vitro-in vivo correlations are missing. Frequently used in vitro models and problems in obtaining in vivo values to establish such models and to identify the action of formulations in vivo are discussed. It may be concluded that major obstacles to link in vitro parameters on in vivo action include lack of treatment adherence and incorrect use of inhalers by patients, variation in inhaler performance, changes by humidity, uncertainties about lung deposition, and difficulties to measure drug levels in epithelial lining fluid and tissue. Physiologically more relevant in vitro models, improvement in inhaler performance, and better techniques for in vivo measurements may help to better understand importance and interactions between individual in vitro parameters in pulmonary delivery.

Development of an In Vitro System to Study the Interactions of Aerosolized Drugs with Pulmonary Mucus

“…Those variations might be related to changes in the viscosity of the test solutions and the geometry of the spray with the investigated compounds. In a clinical scenario, if one considers 20-50% of the dose emitted from the inhaler reach the lungs [25], a typical patchy drug distribution [25] and the surface area of the upper airways, the deposited dose per surface area is likely to be even lower. However, replicating such doses in vitro is not feasible as they would result in undetectable concentrations of permeated drugs.…”

Preclinical Development of Orally Inhaled Drugs (OIDs)—Are Animal Models Predictive or Shall We Move Towards In Vitro Non-Animal Models?

“…This is due to the fact that, DPIs and pMDIs are breath-actuated and therefore not compatible with animal exposure; whereas for nebulizers modifications are needed in line with the animal model adopted. Thus, our manuscript, which focuses on the potential reduction and replacement of animals studies in OID development, does not discuss the impact of inhalers' performance on the effectiveness of inhalation therapies [34], a current challenge discussed in detail elsewhere [35][36][37][38][39][40][41][42][43][44].…”

Drivers of absolute systemic bioavailability after oral pulmonary inhalation in humans

“…Even though pharmacokinetic modeling has been used successfully to predict pulmonary pharmacokinetics from in vitro properties [15], several obstacles to in vitro-in vivo correlations in pulmonary drug delivery have been identified [10,16,17].…”