Rupatadine is a second generation anti-H1 antihistamine and PAF antagonist authorised for the treatment of allergic rhinitis and urticaria at the dose of 10 mg. The aim of this study is to assess the pharmacokinetics and safety of rupatadine following single and multiple oral administrations to healthy Japanese subjects.
Methods
This was a phase I, randomised, double-blind, placebo controlled, parallel group study with oral single and multiple doses that were administered to male and female healthy Japanese subjects from 20 to 45 years of age. Twenty seven subjects (nine per each cohort of dose) were randomised in a 3.5:1 ratio to rupatadine (10, 20 and 40 mg) or matching placebo. On Day -1, all subjects received a single dose of placebo, followed by one single daily oral dose on Day 1 and once single daily doses on Days 2 to 5. Plasma samples collected at different time-points throughout the study were analysed by means of a validated LC-MS/MS analytical method to determine rupatadine and UR-12790 and UR-12788 metabolites concentration. Pharmacokinetic parameters were evaluated by using a noncompartmental analysis, and regression models were used to assess dose linearity.
Results
PK exposure after rupatadine administration of single and multiple doses in Japanese subjects was found to increase in a dose dependent manner. The dose proportionality analysis revealed that the 90% CI of slope for Cmax (rupatadine: 0.65-1.23; UR-12790: 0.87-1.38) and AUC0-∞ (rupatadine: 0.75-1.25; UR-12790: 0.80-1.18) on Day 1 and Cmax (rupatadine: 0.55-1.19; UR-12790: 0.89-1.24 ) and AUC0-tau (rupatadine: 0.75-1.22; UR-12790: 0.83-1.20) on Day 5 for rupatadine and UR-12790 were very close to the range 0.8 to 1.25 and did clearly include 1. Single and multiple oral doses of rupatadine were well tolerated. There were no serious adverse events in this study and no subject withdrew due to safety reasons or any other reasons.
Conclusions
The PK data are not incompatible with dose proportionality and appear to be even more conclusive after repeated doses instead of single doses. Additionally, the PK values in Japanese show similarity to the historic values obtained in Caucasian studies. Rupatadine was safe and well tolerated by Japanese subjects. There were no SAEs in this study and no subject withdrawals due to AEs or any other reason.