Verlängerung der QT-Zeit
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Eklärungen für Patienten zu den Wirkstoffen
Für die Kombination von Abarelix und Aripiprazol liegen uns keine zusätzlichen Warnhinweise vor. Bitte konsultieren Sie zusätzlich die jeweiligen Fachinformationen.
|Aripiprazol||1 [0.48,2.58] 1||1|
Die genannten Expositionsveränderungen beziehen sich jeweils auf Veränderungen der Plasmakonzentrations-Zeit-Kurve [ AUC ]. Für Abarelix erwarten wir keine Veränderung der Exposition, wenn eine Kombination mit Aripiprazol (100%) erfolgt. Für Aripiprazol erwarten wir keine Veränderung der Exposition, wenn eine Kombination mit Abarelix (100%) erfolgt. Die AUC liegt dabei je nach CYP2D6
Für die Berechnung der individuellen Expositionsveränderungen durch die Wechselwirkungen werden als Ausgangsbasis die pharmakokinetischen Parameter der durchschnittlichen Population verwendet.
Für Abarelix ist die Bioverfügbarkeit nicht bekannt. Die terminale Halbwertszeit [ t12 ] ist mit 316.8 Stunden eher lang und konstante Plasmaspiegel [ Css ] werden erst nach mehr als 1267.2 Stunden erreicht. Die Proteinbindung [ Pb ] ist mit 97.5% stark. Die Metabolisierung über Cytochrome wird aktuell noch bearbeitet.
Aripiprazol hat eine hohe orale Bioverfügbarkeit [ F ] von 85%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell wenig verändern. Die terminale Halbwertszeit [ t12 ] ist mit 99 Stunden eher lang und konstante Plasmaspiegel [ Css ] werden erst nach mehr als 396 Stunden erreicht. Die Proteinbindung [ Pb ] ist mit 99% sehr stark und das Verteilungsvolumen [ Vd ] ist mit 404 Liter sehr gross, da die Substanz eine tiefe hepatische Extraktionsrate von 0.04 besitzt, kann eine Verdrängung aus der Proteinbindung [Pb] im Rahmen einer Interaktion die Exposition erhöhen. Die Metabolisierung findet unter anderem über CYP2D6 und CYP3A4 statt und der aktive Transport erfolgt insbesondere über PGP.
|Serotonerge Effekte a||0||Ø||Ø|
Bewertung: Gemäss unseren Erkenntnissen erhöhen weder Abarelix noch Aripiprazol die serotonerge Aktivität.
|Kiesel & Durán b||1||Ø||+|
Empfehlung: Insbesondere nach einer Dosiserhöhung und bei Dosierungen im oberen therapeutischen Bereich sollte vorsichtshalber auf anticholinerge Symptome geachtet werden.
Bewertung: Aripiprazol beeinflusst das anticholinerge System nur mild. Das Risiko für ein anticholinerge Syndrom ist bei dieser Medikation eher als gering einzustufen, wenn die Dosierung sich im üblichen Bereich befindet. Gemäss unseren Erkenntnisse erhöht Abarelix nicht die anticholinerge Aktivität.
Verlängerung der QT-Zeit
Bewertung: In Kombination können Abarelix und Aripiprazol potentiell ventrikuläre Arrhythmien vom Typ Torsades de pointes auslösen.
Erbrechen (7%): Aripiprazol
Schwindel (7%): Aripiprazol
Tremor (6.9%): Aripiprazol
Malignes neuroleptisches Syndrom: Aripiprazol
Transitorische ischämische Attacke: Aripiprazol
Unruhe (7%): Aripiprazol
Verschwommenes Sehen (5.5%): Aripiprazol
Diabetes mellitus: Aripiprazol
Orthostatische Hypotonie: Aripiprazol
Diabetische Ketoazidose: Aripiprazol
Basierend auf Ihren
Abstract: BACKGROUND AND OBJECTIVE: Patients with schizophrenia or bipolar disorder who are experiencing acute behavioural emergencies often require intramuscular injection of antipsychotics for rapid symptom resolution. The efficacy and tolerability of intramuscular aripiprazole injection has been established in agitated inpatients with schizophrenia or bipolar I disorder. The main objective of the two clinical pharmacology studies reported here was to evaluate the pharmacokinetics of aripiprazole after intramuscular dosing in healthy subjects and in patients with schizophrenia, and after intravenous and oral dosing in healthy subjects. SUBJECTS AND METHODS: Study 1 was an open-label, randomized, three-treatment crossover study in healthy subjects (n = 18) to assess the bioavailability and pharmacokinetics of intramuscular aripiprazole 5 mg and oral aripiprazole 5 mg relative to intravenous aripiprazole 2 mg. Study 2 was an open-label, nonrandomized, escalating-dose study in patients with schizophrenia (n = 32) to evaluate the pharmacokinetics of intramuscular aripiprazole across a range of doses (from 1 mg to 45 mg). MAIN OUTCOME MEASURES: The noncompartmental pharmacokinetic parameters for plasma concentrations of aripiprazole and its active metabolite dehydro-aripiprazole were determined. Safety and tolerability data are also summarized. RESULTS: In study 1, the geometric mean values for the absolute bioavailability of aripiprazole following oral and intramuscular administration were 0.85 and 0.98, respectively. Intramuscular aripiprazole demonstrated more rapid attainment of plasma aripiprazole concentrations than oral aripiprazole (78% and 5% of peak plasma concentration [C(max)] values at 0.5 hours postdose, respectively). The area under the plasma concentration-time curve (AUC) in the first 2 hours was 90% higher after intramuscular administration than after oral administration. For dehydro-aripiprazole, the AUC over the collection interval values were higher, the times to reach the C(max) values were later and the C(max) values were similar for the intramuscular and oral formulations. In study 2, the proportionality of the C(max) and AUC to doses ranging from 1 mg to 45 mg suggests a linear pharmacokinetic profile for intramuscular aripiprazole. CONCLUSION: More rapid absorption was observed following intramuscular aripiprazole injection than following oral dosing. These results support the recently reported efficacy of intramuscular aripiprazole for managing agitation in patients with schizophrenia or bipolar I disorder.
Abstract: BACKGROUND AND OBJECTIVES: Two studies were conducted to investigate whether the pharmacokinetics of the atypical antipsychotic aripiprazole were altered in individuals with hepatic or renal impairment compared with those with normal hepatic or renal function. STUDY DESIGN: Two open-label, single-dose studies. STUDY SETTING: Clinical research unit. PATIENTS: Study 1: Subjects with normal hepatic function (n = 6) and subjects with hepatic impairment (Child-Pugh class A [mild, n = 8], B [moderate, n = 8] or C [severe, n = 3]). Study 2: Subjects with normal renal function (creatinine clearance >80 mL/min; n = 7) and subjects with severe renal impairment (creatinine clearance <30 mL/min; n = 6). TREATMENT: Single oral dose of aripiprazole 15 mg. PHARMACOKINETIC ANALYSES: Noncompartmental pharmacokinetic analysis was performed using plasma aripiprazole and dehydro-aripiprazole concentration-time data. MAIN OUTCOME MEASURES: Study 1 (hepatic impairment study): apparent oral clearance of unbound drug (CL/Fu) and the maximum plasma concentration (Cmax) of aripiprazole; Study 2 (renal impairment study): CL/Fu, Cmax and renal clearance (CL(R)). Safety assessments included 12-lead ECGs, vital sign monitoring, clinical laboratory measurements and assessment of adverse events.f RESULTS: In the hepatic impairment study, the mean total Cmax of aripiprazole was significantly lower in subjects with severe hepatic impairment compared with those with normal hepatic function (p = 0.04). The fraction of aripiprazole unbound (fu) was significantly greater for subjects with mild (p = 0.02) or severe hepatic impairment (p < 0.01) but not for those with moderate hepatic impairment (p = 0.09) compared with healthy controls. There were no meaningful differences in either the Cmax of unbound aripiprazole or CL/Fu between groups. The mean CL(R) of aripiprazole was negligible (0.04 mL/h/kg in controls and 0.19 mL/h/kg in patients with severe hepatic impairment). In the renal impairment study, the mean total Cmax values were numerically higher (approximately 40%) and the area under the plasma aripiprazole concentration-time curve from time zero to infinity was lower (approximately 19%) in renally impaired subjects versus those with normal renal function; the fu was comparable between groups. Aripiprazole CL(R) was approximately 3-fold higher in renally impaired subjects, but this difference was not statistically significant. No deaths or serious adverse events were reported during either study. CONCLUSION: A single aripiprazole 15-mg dose was well tolerated. There were no meaningful differences in aripiprazole pharmacokinetics between groups of subjects with normal hepatic or renal function and those with either hepatic or renal impairment. Adjustment of the aripiprazole dose does not appear to be required in populations with hepatic or renal impairment.
Abstract: OBJECTIVE: To describe a case of torsades de pointes (TdP) in a patient treated with aripiprazole. CASE SUMMARY: A 42-year-old white male with schizophrenia, diabetes, hypertension, and a history of stroke was admitted to the intensive care unit following 2 days of fever, diarrhea, and altered mental status. Following the resolution of his acute illness, previous therapy with quetiapine 400 mg orally at bedtime was resumed for schizophrenia and presumed delirium. Quetiapine was discontinued after 1 dose because of QTc interval prolongation. Twenty-three days later, with a baseline QTc interval of 414 milliseconds, aripiprazole 2.5 mg orally once daily was initiated. Following 5 days of aripiprazole therapy, the patient had a cardiac arrest due to TdP. Normal sinus rhythm was restored after 30 seconds of cardiopulmonary resuscitation, 1 shock of 200 Joules, and 4 g of intravenous magnesium sulfate. Serial electrocardiographs obtained after aripiprazole discontinuation revealed resolution of QTc interval prolongation. DISCUSSION: Aripiprazole is a second-generation antipsychotic that may be selected for patients with prolonged QTc intervals and at risk for TdP. Data from trials indicate that aripiprazole has minimal effects on the QTc interval. However, in this case, aripiprazole was associated with TdP in a patient with minimal risk factors. The Naranjo probability scale was used to determine a probable association between aripiprazole and the development of TdP. To our knowledge, this is the first reported case of TdP associated with the use of aripiprazole. CONCLUSIONS: Five days of low-dose aripiprazole therapy was associated with the development of TdP in a man with minimal risk factors. Clinicians should be aware of this potential adverse drug event with aripiprazole.
Abstract: OBJECTIVE: We examined sex differences in the effect of olanzapine (OLZ), risperidone (RIS), aripiprazole (ARP), or quetiapine (QTP) on mean corrected QT (QTc) intervals among 222 patients with schizophrenia. METHODS: Subjects were patients with schizophrenia who were treated with either OLZ (n = 69), RIS (n = 60), ARP (n = 62), or QTP (n = 31). Electrocardiographic measurements were conducted, and the QT interval was corrected using Bazett's correction formula. RESULTS: The mean QTc interval of the QTP group was significantly longer than that of the RIS group (p = 0.002) or ARP group (p = 0.029). The mean QTc interval of the OLZ group was also significantly longer than that of the RIS group (p = 0.006). In female participants, the difference in the mean QTc interval among the four second-generation antipsychotic (SGA) groups was statistically significant (p = 0.002), whereas in male patients, there was no significant difference in the mean QTc interval among the four SGA groups. Post hoc analyses showed that sex differences in QTc interval were observed only in OLZ treatment group (p = 0.007). CONCLUSION: To our knowledge, this is the first study to demonstrate sex differences in the effect of four SGAs on the QTc interval.
Abstract: Dopamine partial agonism and functional selectivity have been innovative strategies in the pharmacological treatment of schizophrenia and mood disorders and have shifted the concept of dopamine modulation beyond the established approach of dopamine D2 receptor (D2R) antagonism. Despite the fact that aripiprazole was introduced in therapy more than 12 years ago, many questions are still unresolved regarding the complexity of the effects of this agent on signal transduction and intracellular pathways, in part linked to its pleiotropic receptor profile. The complexity of the mechanism of action has progressively shifted the conceptualization of this agent from partial agonism to functional selectivity. From the induction of early genes to modulation of scaffolding proteins and activation of transcription factors, aripiprazole has been shown to affect multiple cellular pathways and several cortical and subcortical neurotransmitter circuitries. Growing evidence shows that, beyond the consequences of D2R occupancy, aripiprazole has a unique neurobiology among available antipsychotics. The effect of chronic administration of aripiprazole on D2R affinity state and number has been especially highlighted, with relevant translational implications for long-term treatment of psychosis. The hypothesized effects of aripiprazole on cell-protective mechanisms and neurite growth, as well as the differential effects on intracellular pathways [i.e. extracellular signal-regulated kinase (ERK)] compared with full D2R antagonists, suggest further exploration of these targets by novel and future biased ligand compounds. This review aims to recapitulate the main neurobiological effects of aripiprazole and discuss the potential implications for upcoming improvements in schizophrenia therapy based on dopamine modulation beyond D2R antagonism.
Abstract: BACKGROUND: Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level. METHODS: A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well. RESULTS: The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects. CONCLUSIONS: The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation.