Development of orally administered fixed dose combination (FDC) products: Pharmacokinetic & biopharmaceutical considerations

Combination drug therapy has been shown to be beneficial in chronic multifactorial diseases, infectious diseases and in the treatment of comorbid conditions. Some drug combinations have also been developed to improve the bioavailability of the active components by combining with drug metabolizing enzyme inhibitors. Fixed dose combinations (FDC) offer advantages of better efficacy, ease of administration and patient compliance, while combination therapy generally improves efficacy. For the development of FDCs the primary consideration is the approval status of the drugs to be combined to develop an appropriate strategy. Subsequently, the dose strengths of the individual components need to be considered to be able to allow flexibility of dosing. In order to successfully develop FDC products, demonstration of bioequivalence (BE) to the individual free combinations and lack of pharmacokinetic/pharmacodynamic (PK/PD) drug interaction are essential. Therefore, the development of FDCs requires a good understanding of the biopharmaceutical properties, drug pharmacokinetics and their metabolic pathways. The formulation development program involves pilot stage program followed by registration BE studies with a requirement for food effect bioavailability studies. The regulatory requirements may be challenging in scenarios where two new chemical entities (NCE) are to be combined. Developing a good strategy and designing appropriate trials to evaluate the formulations, drug-drug interactions and bioavailability are critical to the development of FDCs. This review article summarizes the clinical and regulatory requirements of clinical pharmacokinetics/ biopharmaceutics studies in the development of FDCs and challenges that arise in conduct of these studies with respect to dose selection, sample size calculations and food effect