• drug development;
  • drug discovery;
  • H1 antagonists;
  • insomnia;
  • microdosing;
  • pharmacokinetics


• 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.

• Such studies assume linearity of exposure with dose all the way down to a subtherapeutic dose.

• Previous studies have reported partial success in the use of this technique for assessing human PK of marketed drugs.


• The present study describes the application of the microdosing concept in early drug development for an H1 antagonist programme where having good estimates of human PK and information about the shape of the concentration–time curve was critical for compound selection.

• 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.

• To our knowledge, this is the first example of the use microdosing technique for compound selection.

AIMS To evaluate the pharmacokinetics (PK) of five H1 receptor antagonists in human volunteers after a single oral and intravenous (i.v.) microdose (0.1 mg).

METHODS Five H1 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.

RESULTS The median clearance (CL), apparent volume of distribution (Vd) and apparent terminal elimination half-life (t1/2) of diphenhydramine after an i.v. microdose were 24.7 l h−1, 302 l and 9.3 h, and the oral Cmax and AUC0–∞ 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.

CONCLUSIONS Human microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection.