A pharmacokinetic evaluation of five H1 antagonists after an oral and intravenous microdose to human subjects

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT center dot Human microdosing studies with novel drug candidates offer an opportunity to evaluate their pharmacokinetic (PK) behaviour early in drug development and before committing to the expense of clinical Phase I-enabling activities. center dot Such studies assume linearity of exposure with dose all the way down to a subtherapeutic dose. center dot Previous studies have reported partial success in the use of this technique for assessing human PK of marketed drugs. WHAT THIS STUDY ADDS center dot The present study describes the application of the microdosing concept in early drug development for an H-1 antagonist programme where having good estimates of human PK and information about the shape of the concentration-time curve was critical for compound selection. center dot Microdosing data were generated for four novel compounds and one reference compound, and the data were used for advancing the compound with the most favourable PK properties. center dot To our knowledge, this is the first example of the use microdosing technique for compound selection. To evaluate the pharmacokinetics (PK) of five H-1 receptor antagonists in human volunteers after a single oral and intravenous (i.v.) microdose (0.1 mg). Five H-1 receptor antagonists, namely NBI-1, NBI-2, NBI-3, NBI-4 and diphenhydramine, were administered to human volunteers as a single 0.1-mg oral and i.v. dose. Blood samples were collected up to 48 h, and the parent compound in the plasma extract was quantified by high-performance liquid chromatography and accelerator mass spectroscopy. The median clearance (CL), apparent volume of distribution (V-d) and apparent terminal elimination half-life (t(1/2)) of diphenhydramine after an i.v. microdose were 24.7 l h(-1), 302 l and 9.3 h, and the oral C-max and AUC(0-infinity) were 0.195 ng ml(-1) and 1.52 ng h ml(-1), respectively. These data were consistent with previously published diphenhydramine data at 500 times the microdose. The rank order of oral bioavailability of the five compounds was as follows: NBI-2 > NBI-1 > NBI-3 > diphenhydramine > NBI-4, whereas the rank order for CL was NBI-4 > diphenhydramine > NBI-1 > NBI-3 > NBI-2. Human microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection.