ABSTRACT
Orally inhaled drug products (OIDPs) play a great role in the pharmacological treatment of chronic obstructive pulmonary disease (COPD) and asthma. There is an unmet clinical need for OIDPs. Pharmacodynamics-Bioequivalence studies (PD-BE) are recommended by several national guidelines as important research methods for bioequivalence study of OIDPs. It can effectively bridge the gap between in vitro studies and PK-BE studies in evaluating the efficacy and safety consistency of generic drugs with the original drugs. There are two research methods for PD-BE, using a diastolic model or an excitation model. The different methods use different metrics to evaluate efficacy. The more commonly used metrics include Forced Expiratory Volume in the First Second (FEV1), Specific Airway Conductance (sGaw), Peripheral Airway Resistance (R5-20), and stimulant concentration/dose (PC20/PD20). PD-BE studies using FEV1 as an efficacy metric is also recommended by the FDA (Food and Drug Administration), EMA (European Medicines Agency) and NMPA (National Medical Products Administration) guidelines and is widely accepted by investigators. In such PD-BE studies, the trial protocols for different OIDPs drugs are relatively consistent in terms of trial design, trial data processing, and equivalence evaluation criteria, while there are detailed differences in terms of target population, single/multiple dosing, dose administration, and collection site design. This paper reviews the progress of PD-BE studies in the bioequivalence evaluation of OIDPs by combining national guidelines and PD-BE-related studies of OIDPs published in the last five years, with a view to providing important theoretical information for PD-BE studies of OIDPs.
ABSTRACT
Orally inhaled drug products (OIDPs) have a pivotal position and great clinical demand in the treatment of asthma and chronic obstructive pulmonary disease. The development of local generic drugs which are bioequivalent to branded drugs in efficacy and safety while with less price will not only help to solve the problem of drug accessibility, but also greatly reduce the public health burden.OIDPs are complex combinations of formulation and device, and have special drug delivery route and characteristic of local release. Thus, generic drugs of OIDPs are difficult to develop and get registration. Until now, Food and Drug Administration (FDA), European Medicines Association (EMA), Health Canada (HC) and National Medical Products Administration (NMPA) all consider that pharmacokinetics (PK) method can be used to evaluate systemic exposure (safety) in human bioequivalence (BE) study of OIDPs, but there is no consensus on its role in the evaluation of pulmonary deposition (efficacy). The possible reason lies in that the efficacy of OIDPs is determined by both the amount and the region of drug pulmonary deposition. Nevertheless, PK study is still more sensitive and economical in assessing potential differences among products, when compared with pharmacodynamics or clinical endpoint study. Here we mainly compared the domestic and international guidelines and evaluation methods of OIDPs BE study, and introduced the experimental design of PK study and its application and progress in lung deposition study.