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 granisetron and abarelix. Please also consult the relevant specialist information.
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 granisetron, when combined with abarelix (100%). We do not expect any change in exposure for abarelix, when combined with granisetron (100%).
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Granisetron has a mean oral bioavailability [ F ] of 60%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is 8.5 hours and constant plasma levels [ Css ] are reached after approximately 34 hours. The protein binding [ Pb ] is rather weak at 65%. The metabolism mainly takes place via CYP3A4 and the active transport takes place partly via OATP1A2 and PGP.
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.
|Serotonergic Effects a||1||+||Ø|
Recommendation: As a precautionary measure, symptoms of serotonergic overstimulation should be taken into account, especially after increasing the dose and at doses in the upper therapeutic range.
Rating: Granisetron has a mild effect on the serotonergic system. The risk of a serotonergic syndrome can be classified as low with this medication if the dosage is in the usual range. According to our knowledge, abarelix does not increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our knowledge, neither granisetron nor abarelix increase anticholinergic activity.
QT time prolongation
Rating: In combination, granisetron and abarelix can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||gra||aba|
|Atrial fibrillation||0.0 %||0.01||n.a.|
|Hypersensitivity reaction||0.0 %||0.01||n.a.|
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: BACKGROUND: Regulatory concern about potential QT-interval prolongation by serotonin-receptor antagonist antiemetics prompted product-label changes. The first-generation serotonin-receptor antagonist granisetron is available in oral (PO), intravenous (IV), and transdermal formulations. APF530 is a formulation that provides sustained release of granisetron when administered as a single subcutaneous (SC) injection. The Phase I study reported here evaluated effects of APF530 on electrocardiographic intervals. METHODS: This single-site, double-blind, placebo-controlled, four-period crossover trial randomized healthy men and women to receive varying sequences of APF530 1 g SC, granisetron 50 μg/kg IV, moxifloxacin 400 mg PO, and placebo. Subjects were assessed for 49 hours after each treatment. The primary objective was to evaluate differences between baseline-adjusted, heart rate-corrected QT-interval change using the Fridericia rate correction (dQTcF) for APF530 1 g SC and placebo. Electrocardiograms were performed at various times throughout the assessment period. Pharmacokinetics and safety were evaluated. RESULTS: The upper one-sided 95% confidence interval (CI) for mean baseline-adjusted dQTcF at each post-dose time point between APF530 and placebo excluded 10 ms, indicating that APF530 1 g SC had no clinically significant effect on QTcF. Maximum observed QTcF change was 4.15 ms (90% CI, 0.94 to 7.36) at Hour 3. No clinically significant changes in other electrocardiogram intervals were observed. APF530 SC pharmacokinetics were as expected, with slow absorption (maximum plasma concentration 35.8 ng/mL, median time to maximum plasma concentration 11.1 hours) and slow elimination (mean half-life 18.6 hours; systemic clearance 20.2 L/hour) of granisetron versus the expected early peak concentration and elimination of granisetron IV. APF530 SC was well tolerated. Adverse events, most commonly constipation and SC injection-site reactions, were generally mild and quickly resolved. CONCLUSION: APF530 1 g SC did not induce clinically significant QTcF interval prolongation or changes in the other electrocardiogram intervals, and was well tolerated at twice the recommended dose.
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.