Bioequivalence challenges in development of fixed-dose combination products: looking beyond reformulation

Abstract

Introduction: Bioequivalence study is a critical step in the development of novel fixed-dose combination products (FDCPs). While bioequivalence of prototype FDCP to the approved monocomponent products facilitates speedier development and approval, lack of bioequivalence often leads to development delays due to reformulation.

Areas covered: Pharmacokinetic (PK) interaction is one of those issues that often have the potential to completely derail the product development process. The objective of the present article is to highlight PK challenges along with strategies to resolve them.

Expert opinion: A rationale development approach that integrates formulation and clinical insight, so as to understand the clinical significance of non-bioequivalence, would help to minimize the development timeline. While bioequivalence should always be the initial goal in the formulation development, failure to meet it should not immediately lead to reformulation. Instead, evaluating the PK of actives in FDCPs in approved market products, and their consequent clinical implications, would help to make rationale and pragmatic decisions. Such an approach will facilitate the initiation of clinical studies, without increasing the risk of failing to meet safety and efficacy end points, and in turn will significantly improve the productivity.

Keywords:

• bioequivalence
• clinical significance
• fixed-dose combination
• pharmacokinetic interaction
• reformulation