Concentration-Effect Modelling of Blood-Pressure in Early Stage Trials

[Speaker] Jorg Taubel:1,2
[Co-author] Ulrike Lorch:1, Georg Ferber:3
1:Richmond Pharmacology Ltd, UK, 2:St Georges University of London, UK, 3:Statistik Georg Ferber, Switzerland

Background: Drug-induced hypertension is a serious toxic effect of several medication classes such as sympathetomimetics, corticosteroids and vasoconstrictors, therefore assessment of a concentration-effect relationship for investigational medical products is valuable where vascular effects are possible.
Method: The diurnal variation of blood pressure (BP) was characterized, in a randomized double-blind two period crossover bridging study of a cholinomimetic agent being developed for use in Alzheimer's disease, involving single and multiple ascending dose parts. Only the latter included a placebo arm. The study was conducted in 54 male volunteers (equal numbers of Japanese and Caucasian subjects) and included the characterization of the change in diastolic (DBP) and systolic BP (SBP) on investigational medical product (IMP) exposure.
Results: There was a diurnal variation with a marked rise in the first hour after dosing that peaked 4 hours thereafter with a slow recovery that returned to baseline after 24h.
The statistical analysis of the concentration-effect (CE) was performed using a primary linear mixed effects model with fixed effects: deltaBP ~ C*race + T + BL + race
where deltaBP is the change from baseline of the respective BP measure, C is the plasma concentration of IMP, race is a two-level factor (Caucasian and Japanese) and T is a discrete time effect with one level for each time point. Identical time points in the two periods have the same level. BL is baseline value for each subject and period, with the mean across subjects and periods subtracted with no fixed intercept.
The CE model for SBP suggests a minimal dependence of blood pressure on IMP exposure, with a marginally significant slope for Caucasians and an even smaller, non-significant value for the Japanese subjects (Fig 1). This analysis excludes significant effects for DBP for any of the concentrations seen in this study and no significant differences between races can be detected.
Conclusion: The SBP profile includes diurnal rhythms and the study emphasizes the potential influence of the IMP on SBP well beyond the initial exposure. These BP assessments represent novel opportunities for inclusion in early phase studies.

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