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 pimozide. 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 abarelix, when combined with pimozide (100%). We do not expect any change in exposure for pimozide, when combined with abarelix (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.
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.
Pimozide has a mean oral bioavailability [ F ] of 45%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather long at 55 hours and constant plasma levels [ Css ] are only reached after more than 220 hours. The therapeutic window is narrow and the safety margin is therefore small. Even small changes in exposure can increase the risk of toxicity. Protein binding [ Pb ] is not known. The metabolism takes place via CYP1A2, CYP2D6 and CYP3A4, among others and the active transport takes place in particular via PGP.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither abarelix nor pimozide increase serotonergic activity.
|Kiesel & Durán b||1||Ø||+|
Recommendation: As a precaution, attention should be paid to anticholinergic symptoms, especially after increasing the dose and at doses in the upper therapeutic range.
Rating: Pimozide only has a mild effect on the anticholinergic system. The risk of anticholinergic syndrome with this medication is rather low if the dosage is in the usual range. According to our knowledge, abarelix does not increase anticholinergic activity.
QT time prolongation
Rating: In combination, abarelix and pimozide can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||aba||pim|
|Orthostatic hypotension||1.0 %||n.a.||+|
Tardive dyskinesia: pimozide
Ineffective thermoregulation: pimozide
Neuroleptic malignant syndrome: pimozide
Blurred vision: pimozide
Epithelial keratopathy: pimozide
Urinary retention: pimozide
Nasal congestion: pimozide
Paralytic ileus: pimozide
Lupus erythematosus: pimozide
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: Pimozide is a diphenylpiperidine neuroleptic with well characterized cardiovascular side effects including QT prolongation. So far, life-threatening cardiac arrhythmias, in particular torsades de pointes, have not been described in patients treated with pimozide. The authors describe a patient in whom torsades de pointes developed after the ingestion of 800 mg pimozide as a suicide attempt. After intravenous treatment with lidocaine and magnesium, the patient recovered completely and the QT interval had normalized 5 days after the intoxication. Potential mechanisms leading to torsades de pointes in patients treated with pimozide are discussed.
Abstract: BACKGROUND: The use of pimozide is associated with prolongation of the QT interval and fatal ventricular arrhythmia. We recently reported 2 fatal cases in patients taking pimozide and clarithromycin and we have shown that clarithromycin inhibits CYP3A-mediated metabolism of pimozide in vitro. In this study, we examined the effect of clarithromycin on pimozide pharmacokinetics and QT interval changes in a total of 12 healthy subjects (7 men and 5 women), documented as extensive metabolizers or poor metabolizers of CYP2D6. METHODS: In a randomized, double-blind placebo-controlled crossover design, subjects were given a single 6-mg oral dose of pimozide after 5 days of treatment with clarithromycin (500 mg twice a day) or a placebo pill. Blood samples were obtained before and for 96 hours after pimozide administration, and plasma pimozide and clarithromycin concentrations were measured by HPLC. Electrocardiograms for the analysis of the QTc intervals were recorded immediately before each blood sample. RESULTS: Pimozide significantly lengthened QTc interval in the first 20 hours in both the placebo-treated groups (delta QTcmax = 13.3 +/- 5.3 ms; P = .003) and clarithromycin-treated groups (delta QTcmax = 15.7 +/- 9.5 ms; P = .005) compared with baseline values. This is consistent with an effect of the parent drug. Clarithromycin caused a significant increase in the peak plasma concentration (P = .015), terminal elimination half-life (P = .003), and area under the plasma concentration-time curve (P = .024) and a decrease in the clearance (P = .029) of pimozide. Mean QTcmax observed within 20 hours of pimozide administration was significantly greater in the clarithromycin-treated group (23.8 +/- 12.2 ms; P = .0397) than in the placebo-treated group (16.8 +/- 6 ms). There was no significant effect of CYP2D6 or gender on the pharmacokinetics or pharmacodynamics of pimozide. CONCLUSIONS: A single 6-mg oral dose of pimozide resulted in measurable QT interval changes. Clarithromycin inhibited CYP3A-mediated pimozide metabolism and the resulting elevation in plasma concentrations may increase the risk of pimozide cardiotoxicity.
Abstract: Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.
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.