Stable Isotopically Labeled Intravenous Microdose Pharmacokinetic Trials as a Tool to Assess Absolute Bioavailability: Feasibility and Paradigm to Apply for Protein Kinase Inhibitors in Oncology

Absolute bioavailability is defined as a measure of the extent to which the administered drug is absorbed systemically and becomes available in the general circulation compared with intravenously administered drug.1 For orally administered drugs, obtaining data on absolute bioavailability is an important component of clinical drug development. Low bioavailability may indicate poor solubility and/or permeability, membrane transport, and/or enzymatic metabolism.1, 2 Knowledge on absolute bioavailability in an early stage of clinical development is therefore considered essential to allow for the development of optimal drug formulations. Despite the clear usefulness, absolute bioavailability determination is not mandatory and therefore not a routine part of clinical drug development.1 For the group of orally administered tyrosine kinase inhibitors, an important oral drug class in oncology, it was identified that for more than half the drugs registered up to 2014, an absolute bioavailability trial was not performed during clinical drug development.2 The main reason for this might be that the assessment of absolute bioavailability requires the formulation and safety testing of an intravenous formulation at therapeutic strength, which serves as a reference to the oral formulation. Technical issues (eg, poor solubility) as well as costs associated with development and safety testing of an intravenous formulation make it often omitted. The microdose trial design may aid overcoming these problems by making use of an intravenous microdose formulation, defined as less than 1/100th of the therapeutic dose with a maximum of 100 μg. Because microdose studies involve exposure to very small amounts of drug, additional safety testing of the intravenous formulation is not required. Furthermore, drug solubility issues are most often no longer a problem, as only a 100‐μg amount needs to be dissolved into an intravenous formulation.3, 4 Originally, the major concern with microdosing has been the potential for nonlinear pharmacokinetics between the microdose and the therapeutic dose.5 The introduction of stable isotopically labeled microdosing has made it possible to overcome this problem.6 By allowing simultaneous administration of a labeled microdose next to a therapeutic unlabeled dose, this new approach has provided opportunity to further improve absolute bioavailability trial designs. In this review, we describe the way clinical absolute bioavailability trials are conducted using both a conventional trial design and a microdose trial design. The use of a stable isotopically labeled microdose (SILM) in combination with ultrasensitive liquid chromatography–tandem mass spectrometry (LC‐MS/MS) as an analytical technique is described in more detail. For the group of orally administered small‐molecule protein kinase inhibitors (smPKIs), we investigated whether absolute bioavailability was determined during clinical drug development and if a SILM trial design in combination with LC‐MS/MS would have been feasible. We conclude by discussing how the use of SILM studies can affect the execution of absolute bioavailability trials in the future