Elsevier

Biological Psychiatry

Volume 55, Issue 10, 15 May 2004, Pages 1007-1012
Biological Psychiatry

Original article
Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant

https://doi.org/10.1016/j.biopsych.2004.02.007Get rights and content

Abstract

Background

Aprepitant is a highly selective substance P (neurokinin 1 [NK1] receptor) antagonist that significantly improves the pharmacotherapy of acute and delayed highly emetogenic chemotherapy–induced nausea and vomiting, probably through an action in the brain stem region of the central nervous system. Here, we report the use of positron emission tomography imaging with the NK1 receptor binding–selective tracer [18F]SPA-RQC to determine the levels of central NK1 receptor occupancy achieved by therapeutically relevant doses of aprepitant in healthy humans.

Methods

Two single-blind, randomized, placebo-controlled studies in healthy subjects were performed. The first study evaluated the plasma concentration–occupancy relationships for aprepitant dosed orally at 10, 30, 100, or 300 mg, or placebo (n = 12). The second study similarly evaluated oral aprepitant 30 mg and placebo (n = 4). In each study, dosing was once daily for 14 consecutive days. Data from both studies were combined for analyses. The ratio of striatal/cerebellar [18F]SPA-RQ (high receptor density region/reference region lacking receptors) was used to calculate trough receptor occupancy 24 hours after the last dose of aprepitant.

Results

Brain NK1 receptor occupancy increased after oral aprepitant dosing in both a plasma concentration–related (r = .97; 95% confidence interval [CI] = .94–1.00, p < .001) and a dose-related (r = .94; 95% CI = .86–1.00, p < .001) fashion. High (≥90%) receptor occupancy was achieved at doses of 100 mg/day or greater. The plasma concentrations of aprepitant that achieved 50% and 90% occupancy were estimated as approximately 10 ng/mL and approximately 100 ng/mL, respectively.

Conclusions

Positron emission tomography imaging with [18F]SPA-RQ allows brain NK1 receptor occupancy by aprepitant to be predicted from plasma drug concentrations and can be used to guide dose selection for clinical trials of NK1 receptor antagonists in central therapeutic indications.

Section snippets

Subjects

Healthy male subjects, aged between 18 and 45 years, were enrolled at two study sites (Uppsala University, Uppsala, Sweden and University of Turku, Turku, Finland). History, physical examination, and laboratory assessments were conducted within 3 weeks before study initiation to assess health status. All volunteers were medication free for at least 2 weeks before the initiation of the study and were nonsmokers for at least 6 months before the study.

The studies were reviewed and approved by the

Demographics

In the first dose-ranging study, 12 healthy, white, male subjects (mean age = 26 years [range: 23–41], mean height = 180 cm [range: 167–191], mean weight = 75 kg [range: 66–92]) were randomized to receive either aprepitant 10 mg/day (n = 2), 30 mg/day (n = 3), 100 mg/day (n = 3), 300 mg/day (n = 2), or placebo (n = 2). In the second study, four healthy, white, male subjects (mean age = 24 years [range: 23–25], mean height = 180 cm [range: 173–186], mean weight = 77 kg [range: 72–83]) were

Discussion

These are the first studies to demonstrate a clinically useful method of assessing NK1 receptors and their occupancy by an NK1 receptor antagonist in the human brain in vivo. We used the high affinity and specificity of a novel PET ligand, [18F]SPA-RQ (Hargreaves, 2002, Solin et al.), to assess the strength of the relationship between both dose and plasma concentration of aprepitant (a high-affinity, reversibly binding NK1 receptor antagonist) with receptor occupancy, and then to estimate the

Acknowledgements

These studies were funded by Merck Research Laboratories, West Point, Pennsylvania.

We thank the staff of the Positron Emission Tomography Laboratories at Uppsala and Turku for their help; Dr. Kevin Gingrich for oversight of some of these studies; and Dr. Christopher Lines for assistance with preparing the manuscript.

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