Development of an in vivo target-engagement biomarker for TRPA1 antagonists in humans.
To develop a non-invasive, safe and reproducible target-engagement biomarker for future TRPA1 antagonists in healthy volunteers.



Dose finding (n = 11): 3%, 10%, and 30% cinnamaldehyde (CA) and placebo (= vehicle) was topically applied on the right forearm. One-way ANOVA with post-hoc Bonferroni was used to compare between doses. Reproducibility: 10% CA doses were topically applied during one visit on both arms (n = 10) or during two visits (n = 23) separated by a washout period of 7 days. CA-induced dermal blood flow (DBF) was assessed by laser Doppler imaging (LDI) at baseline and at 10, 20, 30, 40 and 50 min post-CA. Paired t-test was used to compare between arms or visits. Concordance correlation coefficient (CCC) was calculated to assess reproducibility. Data are expressed as percent change from baseline (mean ± 95% CI).



All three doses increased DBF compared to vehicle at all time-points, with the maximum response at 10-20 min post-CA. Dose response was found when comparing AUC0-50minof 30% CA (51 364 ± 8475%*min) with 10% CA (32 239 ± 8034%*min, P = 0.03) and 3% CA (30 226 ± 11 958%*min, P = 0.015). 10% CA was chosen as an effective and safe dose. DBF response to 10% CA was found to be reproducible between arms (AUC0-50min, CCC = 0.91) and visits (AUC0-50min, CCC = 0.83). Based on sample size calculations, this model allows a change in CA-induced DBF of 30-50% to be detected between two independent groups of maximum 10-15 subjects with 80% power.



Evaluation of CA-induced changes in DBF offers a safe, non-invasive and reproducible target-engagement biomarker in vivo in humans to evaluate TRPA1 antagonists.
Centre for Clinical Pharmacology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.
Linde
L
Buntinx
Centre for Clinical Pharmacology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.
Lin
L
Chang
Centre for Clinical Pharmacology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.
Aasim
A
Amin
Department of Cardiovascular Sciences, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.
Bart
B
Morlion
Centre for Clinical Pharmacology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.
Jan
J
de Hoon
D000171:Acrolein / Q000031:analogs & derivatives* / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D015415:Biomarkers; D004305:Dose-Response Relationship, Drug; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D017078:Laser-Doppler Flowmetry; D008297:Male; D008875:Middle Aged; D012039:Regional Blood Flow / Q000187:drug effects*; D015203:Reproducibility of Results; D012867:Skin / Q000098:blood supply; D000074025:TRPA1 Cation Channel / Q000819:agonists; D055815:Young Adult
D015415:Biomarkers; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D000171:Acrolein; C012843:cinnamaldehyde
TRPA1; cinnamaldehyde; inflammation; pain; pharmacodynamics; target-engagement biomarker
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