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Development of an in vivo target‐engagement biomarker for TRPA1 antagonists in humans
Author(s) -
Buntinx Linde,
Chang Lin,
Amin Aasim,
Morlion Bart,
Hoon Jan
Publication year - 2017
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13143
Subject(s) - reproducibility , medicine , concordance correlation coefficient , biomarker , in vivo , washout , urology , analysis of variance , post hoc analysis , coefficient of variation , pharmacodynamics , pharmacokinetics , nuclear medicine , anesthesia , pharmacology , chemistry , chromatography , biochemistry , statistics , mathematics , microbiology and biotechnology , biology
Aim To develop a non‐invasive, safe and reproducible target‐engagement biomarker for future TRPA1 antagonists in healthy volunteers. Methods 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). Results 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 AUC 0–50min of 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 (AUC 0–50min , CCC = 0.91) and visits (AUC 0–50min , 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. Conclusions 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.