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3/25/09 Five compound Phase 0 Human Microdose useful in candidate selection
Date Posted: |
25 Mar 2009 |
Summary: |
February 2009: A pharmacokinetic evaluation of five H1 antagonists after an oral and intravenous microdose to human subjects |
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Published in the British Journal of Clinical Pharmacology, 67:3 / 288–298, 2009
Five H1 antagonists were dosed at a sub-pharmacologic microdose to evaluate the pharmacokinetics (PK) in human volunteers after a single oral and intravenous microdose.
Clearance, volume of distribution, half life and bioavailability of diphenhydramine and four competing compounds was established using Phase 0 Human Microdosing which proved useful for compound selection.
AIMSTo 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–infinity were 0.195 ng ml-1 and 1.52 ng hml-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.
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