Role of Pharmacokinetics in Establishing Bioequivalence for Orally Inhaled Drug Products
O'Connor DK.
Respiratory Drug Delivery 2010. Volume 1, 2010: 245-248.
Abstract:
The Product Quality Research Institute (PQRI) previously sponsored a two-day workshop relating to Demonstrating Bioequivalence of Locally Acting Orally Inhaled Drug Products which reviewed recommendations for demonstrating bioequivalence (BE) in the development of orally inhaled drug products (OIPs) (1). In vitro methods to demonstrate BE, biomarkers, imaging techniques, in vivo approaches to establish local delivery equivalence, and device design similarity were addressed. The workshop highlighted that the utility of pharmacokinetic (PK) studies for the evaluation of local pulmonary delivery equivalence deserved further attention.
The regulatory guidance requirements for demonstrating BE of OIPs vary in the different global regions. In Europe, the EMEA Guideline on the Requirements for Clinical Documentation for Orally Inhaled Products (2) advocates a stepwise approach using in vitro comparisons, followed by lung deposition studies (PK or imaging studies), and finally pharmacodynamic (PD) / clinical effect studies. At each step, if BE is demonstrated, no further studies are required. The Health Canada guidance for second entry short-acting beta agonists (SABA) (3) does not reference PK studies to establish equivalence, while the draft guidance for subsequent market entry of inhaled corticosteroids (ICS) allows for systemic exposure PK studies if the plasma levels are sufficient to enable reliable analytical measurement; otherwise systemic exposure should be determined in a PD study (4). The Food and Drug Administration (FDA) Critical Path Opportunities for Generic Drugs (5) recognizes that the assessment of bioequivalence for locally acting products has presented scientific challenges to the approval of generic products. While there is no specific FDA guidance on demonstrating BE for OIPs, the FDA currently recommends a “Weight-of-Evidence” approach which incorporates qualitative (Q1) and quantitative (Q2) formulation sameness, in vitro testing for the evaluation of the formulation and device performance, PK studies for the evaluation of systemic exposure and PD studies of lung function for local delivery (1).
While BE of solid oral dosage forms intended for systemic delivery is based on in vivo PK supported by comparative in vitro dissolution data, a similar approach has not been adopted for inhaled drugs because the drug detected in the systemic circulation has not been shown to accurately reflect drug delivered to the site(s) of action in the lung. The uncertainty in determination of lung-specific absorption of inhaled drugs has been a major challenge in the acceptance of PK data as the sole indicator of in vivo BE for inhaled drugs. Consequently, clinical endpoints have been suggested for testing pulmonary equivalence despite the fact that these studies are prohibitively expensive and are known to be a relatively insensitive approach to detect differences in product performance. The greatest challenge in adopting this approach with some OIPs (particularly ICSs) is the demonstration of dose response in PD studies, without which the bioassay has no value in the determination of BE. The flat dose-response profiles of ICS represent a challenge and traditional clinical approaches, as well as studies with improved study design (exhaled nitric oxide model (6); asthma stability model (7)), have not yet shown sufficient sensitivity necessary for BE studies.
The objective of this workshop is to evaluate the current state of knowledge and identify gaps in information relating to the potential use of pharmacokinetics (PK) as the sole indicator of in vivo bioequivalence of locally acting OIPs. The strengths of the PK approach to detect differences in product performance compared with in vitro and PD/clinical studies will be addressed.
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