Scientific Rationale for Determining the Bioequivalence of Inhaled Drugs.

In recent years, pathways for the development and approval of bioequivalent inhaled products have been established for regulated markets, including the European Union (EU), and a number of orally inhaled products (OIPs) have been approved in the EU solely on the basis of in vitro and pharmacokinetic data. This review describes how these development pathways are structured and their implications for the treatment of airway diseases such as asthma. The EU guidance follows a stepwise approach that includes in vitro criteria as the first step. If all in vitro criteria are not met, the second step is based on pharmacokinetic evaluations, which include assessments of lung and systemic bioavailability. If all pharmacokinetic criteria are not met, the third step is based on clinical endpoint studies. In this review, the scientific rationale of the European Medicines Agency guidance for the development of bioequivalent OIPs is reviewed with the focus on the development of bioequivalent OIPs in the EU. Indeed, we discuss the advantages and disadvantages of the weight-of-evidence and stepwise approaches. The evidence indicates that the EU guidance is robust and, unlike clinical endpoint studies, the pharmacokinetic studies are far more sensitive to measure the minor differences, i.e. deposition and absorption rates, in drug delivery from the test and reference products and, thus, should be best suited for assessing bioequivalence. The acceptance range of the 90% confidence intervals for pharmacokinetic bioequivalence (i.e. 80-125% for both the area under the plasma concentration-time curve and maximum plasma concentration) represent appropriately conservative margins for ensuring equivalent safety and efficacy of the test and reference products.