Within an absolute bioavailability microdose trial, the oral therapeutic dose designed for clinical use is administered, and the intravenous microdose is administered concomitantly on the approximated maximum plasma concentration from the oral dose (Body?1). medication. 1 For implemented medications orally, obtaining data on overall bioavailability can be an important element of scientific medication advancement. Low bioavailability might suggest poor solubility and/or permeability, membrane transportation, and/or enzymatic GTS-21 (DMBX-A) fat burning capacity. 1 , 2 Understanding on overall bioavailability within an early stage of scientific advancement is therefore regarded essential to enable the introduction of optimum medication formulations. Regardless of the apparent usefulness, overall bioavailability perseverance isn’t necessary rather than a regular component of clinical medication advancement therefore. 1 For the band of implemented tyrosine kinase inhibitors, an important dental medication course in oncology, it had been discovered that for over fifty percent the medications signed up up to 2014, a complete bioavailability trial had not been performed during scientific medication advancement. 2 The primary reason for GTS-21 (DMBX-A) this may 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 Rabbit polyclonal to RFP2 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 g. 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\g 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 chromatographyCtandem mass spectrometry (LC\MS/MS) as an analytical technique is described in more detail. For GTS-21 (DMBX-A) 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. Absolute Bioavailability Trial Design Conventional Absolute Bioavailability Trial Design The absolute bioavailability of novel oral anticancer agents is normally investigated using a 2\period crossover trial design. 1 After intravenous and oral administration of the study drug at therapeutic strength during different dose events, exposure as defined by total area under the plasma concentration\time curve (AUC) is calculated for each dose route. Dividing the equations for the intravenous (iv) and extravascular (ev) administration gives the classical equation for calculating bioavailability, as shown in equation 1: math xmlns:mml=”http://www.w3.org/1998/Math/MathML” display=”block” id=”nlm-math-1″ mrow mi F /mi mspace width=”0.33em” /mspace mo = /mo mfenced separators=”” open=”(” close=”)” mfrac mrow mi mathvariant=”normal” AU /mi msub mi mathvariant=”normal” C /mi mi mathvariant=”normal” ev /mi /msub /mrow mrow mi mathvariant=”normal” AU /mi msub mi mathvariant=”normal” GTS-21 (DMBX-A) C /mi mi mathvariant=”normal” iv /mi /msub mspace width=”0.33em” /mspace /mrow /mfrac /mfenced mspace width=”0.33em” /mspace mspace width=”0.33em” /mspace mo /mo mspace width=”0.33em” /mspace mfenced separators=”” open=”(” close=”)” mfrac mrow mi mathvariant=”normal” Dos /mi msub mi mathvariant=”normal” e /mi mi mathvariant=”normal” iv /mi /msub /mrow mrow mi mathvariant=”normal” Dos /mi msub mi mathvariant=”normal” e /mi mi mathvariant=”normal” ev /mi /msub /mrow /mfrac /mfenced /mrow /math (1) The conventional absolute bioavailability trial design is limited in 2 ways. First, an intravenous formulation at therapeutic strength is required, which is not always available for drugs that are poorly soluble in aqueous solutions, and, if available, requires additional safety testing. Second, the 2\period crossover trial design assumes linear pharmacokinetics GTS-21 (DMBX-A) and equal clearance between the 2 dose events, which is not always the case. A potential way to overcome these problems is provided by the microdosing trial design. 1 Microdose Absolute Bioavailability Trial Design A microdose is defined as 1/100th of the therapeutic dose with a maximum of 100 g. In an absolute bioavailability microdose trial, the oral therapeutic dose intended for clinical use is administered, after which the intravenous microdose is administered concomitantly at the estimated maximum plasma concentration of the oral dose (Figure?1). The absolute bioavailability can then be calculated.
Within an absolute bioavailability microdose trial, the oral therapeutic dose designed for clinical use is administered, and the intravenous microdose is administered concomitantly on the approximated maximum plasma concentration from the oral dose (Body?1)