title: Interactions between active pharmaceutical ingredients and excipients affecting bioavailability: impact on bioequivalence.
abstract: The aim of the present paper is to illustrate the impact that excipients may have on the bioavailability of drugs and to review existing US-FDA, WHO and EMA regulatory guidelines on this topic. The first examples illustrate that small amounts of sorbitol (7, 50 or 60mg) affect the bioavailability of risperidone, a class I drug, oral solution, in contrast to what is stated in the US-FDA guidance. Another example suggests, in contrast to what is stated in the US-FDA BCS biowaivers guideline, that a small amount of sodium lauryl sulphate (SLS) (3.64mg) affects the bioavailability of risperidone tablets, although the reference product also includes SLS in an amount within the normal range for that type of dosage form. These factors are considered sufficient to ensure that excipients do not affect bioavailability according to the WHO guideline. The alternative criterion, defined in the WHO guideline and used in the FIP BCS biowaivers monographs, that asserts that excipients present in generic products of the ICH countries do not affect bioavailability if used in normal amounts, is shown to be incorrect with an example of alendronate (a class III drug) tablets, where 4mg of SLS increases bioavailability more than 5-fold, although a generic product in the USA contains SLS. Finally, another example illustrates that a 2mg difference in SLS may affect bioavailability of a generic product of a class II drug, even if SLS is contained in the comparator product, and in all cases its amount was within the normal range. Therefore, waivers of in vivo bioequivalence studies (e.g., BCS biowaivers, waivers of certain dosage forms in solution at the time of administration and variations in the excipient composition) should be assessed more cautiously.
authors.affiliation: Head of Service on Pharmacokinetics and Generics, Division of Pharmacology and Clinical Evaluation, Department of Human Use Medicines, Spanish Agency for Medicines and Health Care Products, Madrid, Spain. Electronic address: agarciaa@aemps.es.
authors.forename: Alfredo
authors.initials: A
authors.lastname: García-Arieta
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D001702:Biopharmaceutics / Q000379:methods; D005079:Excipients / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D013607:Tablets / Q000737:chemistry / Q000378:metabolism; D013810:Therapeutic Equivalency
chemical_list: D005079:Excipients; D004364:Pharmaceutical Preparations; D013607:Tablets
keywords: Bioavailability; Biowaivers; Drug–excipient interaction; Excipient; Regulatory requirements