Evidence of Distinct Histamine Pharmacodynamic Phenotypes in Children

BACKGROUND Histamine iontophoresis with laser Doppler monitoring (HILD) provides a surrogate endpoint of histamine microvasculature response which is more dynamic and robust than classical epicutaneous histamine challenge. The purpose of this study was to characterize the pharmacodynamics (PD) of histamine in children using HILD. METHODS HILD was performed in children with allergic rhinitis (n=54). PD data were analyzed with a non-linear mixed-effects model (NONMEM v7.2). Effect data (relative maximal response over baseline; EffmaxNt) and time of EffmaxNt; Tmax) were initially evaluated by visualization of time vs. response relationships which revealed apparent sub-groups within the cohort. Differences in model parameters between groups were determined using ANOVA and post-hoc analysis using Tukey’s HSD. Linear regression was used to explore associations between parameters to validate apparent sub-group differences in PD. Data analysis was completed 12/15/11. RESULTS Evaluable data were obtained for N=43 participants 7-17 years of age (mean 12.2 yr). Three distinct histamine response phenotypes were identified; one group (n=7) demonstrated a pattern consistent with an apparent hyper- responsive phenotype that was characterized by significantly higher Tmax, EffmaxNt, and AUEC with respect to microvascular blood flow as a function of time (p\u3c.007). There were no significant differences observed for E 50, and Ke0.Identification of the hyper-responsive subgroup was further validated by a stronger association between AUEC and EffmaxNt (r2=0.86) when compared to the entire cohort (r2= 0.005). CONCLUSION Our data demonstrate the presence of an apparent hyper-responsive phenotype for histamine effect as reflected by HILD monitoring. This “effect phenotype” must be considered in future pediatric studies which are designed to assess the PK-PD relationship for antihistamines, either as a function of age or disease state