QT time prolongation
Adverse drug events
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Explanations of the substances for patients
We have no additional warnings for the combination of abarelix and pitolisant. Please also consult the relevant specialist information.
|Pitolisant||1 [0.49,2.37] 1||1|
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. We do not expect any change in exposure for abarelix, when combined with pitolisant (100%). We do not expect any change in exposure for pitolisant, when combined with abarelix (100%). The AUC is between 49% and 237% depending on the CYP2D6
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
The bioavailability of abarelix is unknown. The terminal half-life [ t12 ] is rather long at 316.8 hours and constant plasma levels [ Css ] are only reached after more than 1267.2 hours. The protein binding [ Pb ] is 97.5% strong. The metabolism via cytochromes is currently still being worked on.
Pitolisant has a mean oral bioavailability [ F ] of 55%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is 20 hours and constant plasma levels [ Css ] are reached after approximately 80 hours. The protein binding [ Pb ] is moderately strong at 93.5%. which is why, with a mean hepatic extraction rate of 0.36, both liver blood flow [Q] and a change in protein binding [Pb] are relevant. The metabolism takes place via CYP2D6 and CYP3A4, among others.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither abarelix nor pitolisant increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our knowledge, neither abarelix nor pitolisant increase anticholinergic activity.
QT time prolongation
Rating: In combination, abarelix and pitolisant can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||aba||pit|
Based on your answers and scientific information, we assess the individual risk of undesirable side effects. These recommendations are intended to advise professionals and are not a substitute for consultation with a doctor. In the restricted test version (alpha), the risk of all substances has not yet been conclusively assessed.
Abstract: OBJECTIVE: The objective of the present study was to compare the effects of pitolisant on QTcF interval in a single ascending dose (SAD) study and a thorough QT (TQT) study. METHODS: The SAD study at three dose levels of pitolisant enrolled 24 males and the TQT study at two dose levels 25 males. Both studies intensively monitored ECGs and pitolisant exposure. Effect on QTcF interval was analysed by Intersection Union Test (IUT) and by exposure-response (ER) analysis. Results from the two studies were compared. RESULTS: In both studies, moxifloxacin effect established assay sensitivity. IUT analysis revealed comparable pitolisant-induced maximum mean (90 % confidence interval (CI)) placebo-corrected increase from baseline (ΔΔQTcF) in both the studies, being 13.3 (8.1; 18.5) ms at 200-mg and 9.9 (4.7; 15.1) ms at 240-mg doses in SAD study and 5.27 (2.35; 8.20) ms at 120-mg dose in TQT study. ER analysis revealed that ER slopes in SAD and TQT studies were comparable and significantly positive (0.031 vs 0.027 ms/ng/mL, respectively). At geometric mean concentrations, bootstrap predicted ΔΔQTcF (90 % CI) were 9.23 (4.68; 14.4) ms at 279 ng/mL (240-mg dose) in the SAD study and 4.97 (3.42; 8.19) ms at 156 ng/mL (120-mg dose) in the TQT study. CONCLUSION: Pitolisant lacked an effect of regulatory concern on QTc interval in both the studies, however analysed, suggesting that the results from the SAD study could have mitigated the need for a TQT study. Our findings add to the growing evidence that intensive ECG monitoring in early phase clinical studies can replace a TQT study.