Pharmacodynamic Studies to Demonstrate Bioequivalence of Oral Inhalation Products

Abstract

In the session on "Pharmacodynamic studies to demonstrate efficacy and safety", presentations were made on methods of evaluating airway deposition of inhaled corticosteroids and bronchodilators, and systemic exposure indirectly using pharmacodynamic study designs. For inhaled corticosteroids, limitations of measuring exhaled nitric oxide and airway responsiveness to adenosine for anti-inflammatory effects were identified, whilst measurement of 18-h area under the cortisol concentration-time curve was recommended for determining equivalent systemic exposure. For bronchodilators, methacholine challenge was recommended as the most sensitive method of determining the relative amount of β-agonist or anti-muscarinic agent delivered to the airways. Whilst some agencies, such as the Food and Drug Administration (FDA), do not require measuring systemic effects when pharmacokinetic measurements are feasible, the European Medicines Agency requires measurement of heart rate and serum potassium, and some require serial electrocardiograms when bioequivalence is not established by pharmacokinetic (PK) studies. The Panel Discussion focused on whether PK would be the most sensitive marker of bioequivalence. Furthermore, there was much discussion about the FDA draft guidance for generic fluticasone propionate/salmeterol. The opinion was expressed that the study design is not capable of detecting a non-equivalent product and would require an unfeasibly large sample size.

Equivalent bronchodilation with budesonide/formoterol combination via Easyhaler and Turbuhaler in patients with asthma

“…methacholine are an alternative way to compare bronchodilator drug efficacy. They have been argued to have steeper dose-response curves, and therefore, being more sensitive than bronchodilation studies [23,24]. There are, however, many methodological challenges related to performing bronchoprotection studies.…”

Rethinking bioequivalence and equivalence requirements of orally inhaled drug products

“…Although this biomarker was hoped to reflect the secondary (latent) mechanism of action of ICS, its response is influenced by many factors, such as collection techniques, disease states, and other patient factors (food, drink, smoking) [38]. Even though there is still some interest in using this biomarker for ICS [39], it is not necessarily recommended anymore by regulatory agencies as studies have revealed the absence of a dose-response relationship between ENO and fluticasone administered at the marketed dosing regimens. The lowest labeled dose (88 mcg twice daily (BID)) was associated with responses on or near the plateau of the dose-response curve and responses did not return to baseline levels after the 14-day washout period [40].…”

Randomized, Double‐Blind, Crossover, Clinical‐End‐Point Pilot Study to Examine the Use of Exhaled Nitric Oxide as a Bioassay for Dose Separation of Inhaled Fluticasone Propionate

“…Since this pilot study was carried out, the dose response of eNO relative to fluticasone propionate in crossover designs has been further investigated. In Hendeles, the work of Daley‐Yates and Kandala was reviewed. They examined change in eNO and average eNO, respectively, in dose‐response models.…”

“…However, Daley‐Yates concluded that eNO still has potential as a measure of drug availability, but it requires further study: “Designs for eNO should be evaluated using the area under the effect curve rather than single time points and also exploring the onset and offset of effect, shorter dosing, and/or once‐daily dosing regimens.”…”

“…Once‐daily dosing is a feature of the study discussed in this article. In addition, a different end point from either of the end points discussed by Daley‐Yates and Kandala was used as described in the Planned Analyses section below.…”