Sommario
71%
|
Farmacocinetica
|
-2% | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Simeprevir | |||||||||||
| Amiodarone | |||||||||||
| Punteggi | -7% | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
|
Estensione di tempo QT
| |||||||||||
|
Effetti anticolinergici
| |||||||||||
|
Effetti serotoninergici
| |||||||||||
|
Effetti avversi del farmaco
|
-20% | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Iperbilirubinemia | |||||||||||
| Nausea | |||||||||||
| Fatica | |||||||||||
Varianti ✨
Per la valutazione computazionalmente intensiva delle varianti, scegli l'abbonamento standard a pagamento.
Aree di applicazione
Spiegazioni per i pazienti
Farmacocinetica
-2%
| ∑ Esposizionea | sim | ami | |
|---|---|---|---|
| Simeprevir | 1.34 [1.34,2.16] 1 | 1.34 | |
| Amiodarone | n.a. | n.a. |
Genotipi rilevanti: 1BCRP
Simbolo (a): variazione x volte dell'AUC
Leggenda (n.a.): Informazioni non disponibili
Simbolo (a): variazione x volte dell'AUC
Leggenda (n.a.): Informazioni non disponibili
I cambiamenti nell'esposizione menzionati si riferiscono ai cambiamenti nella curva concentrazione plasmatica-tempo [AUC]. L'esposizione alla simeprevir aumenta al 134%, se combinato con amiodarone (134%). Non abbiamo rilevato alcun cambiamento nell'esposizione alla amiodarone. Al momento non possiamo stimare l'influenza della simeprevir.
Valutazione:
I parametri farmacocinetici della popolazione media sono utilizzati come punto di partenza per il calcolo delle singole variazioni di esposizione dovute alle interazioni.
La simeprevir ha una biodisponibilità orale media [ F ] del 62%, motivo per cui i livelli plasmatici massimi [Cmax] tendono a cambiare con un'interazione. L'emivita terminale [ t12 ] è piuttosto lunga a 41 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti solo dopo più di 164 ore. Il legame proteico [ Pb ] è molto forte al 99.9% e il volume di distribuzione [ Vd ] è molto grande a 250 litri, Il metabolismo avviene tramite CYP2C19, CYP2C8 e CYP3A4, tra gli altri e il trasporto attivo avviene in parte tramite BCRP, MRP2, OATP1B1, OATP1B3 e PGP.
La amiodarone ha una biodisponibilità orale media [ F ] del 55%, motivo per cui i livelli plasmatici massimi [Cmax] tendono a cambiare con un'interazione. L'emivita terminale [ t12 ] è piuttosto lunga a 1884 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti solo dopo più di 7536 ore. Il legame proteico [ Pb ] è forte al 96%. Il metabolismo avviene tramite CYP2C8 e CYP3A4, tra gli altri e il trasporto attivo avviene in particolare tramite PGP.
Effetti serotoninergici
-0%
| Punteggi | ∑ Punti | sim | ami |
|---|---|---|---|
| Effetti serotoninergici a | 0 | Ø | Ø |
Simbolo (a): Rischio aumentato da 5 punti.
Valutazione: Secondo le nostre conoscenze, né la simeprevir né la amiodarone aumentano l'attività serotoninergica.
Effetti anticolinergici
-0%
| Punteggi | ∑ Punti | sim | ami |
|---|---|---|---|
| Kiesel b | 0 | Ø | Ø |
Simbolo (b): Rischio aumentato da 3 punti.
Valutazione: Secondo i nostri risultati, né la simeprevir né la amiodarone aumentano l'attività anticolinergica.
Estensione di tempo QT
-9%
| Punteggi | ∑ Punti | sim | ami |
|---|---|---|---|
| RISK-PATH c | 3 | Ø | +++ |
Simbolo (c): Rischio aumentato da 10 punti. Occorre rispondere alle domande sui fattori di rischio.
Raccomandazione:
Per poter stimare il rischio individuale di aritmie, si consiglia di rispondere in modo completo alle seguenti
Valutazione: La amiodarone può scatenare aritmie ventricolari de torsionali potenzialmente torsionali. Non conosciamo alcun potenziale di prolungamento dell'intervallo QT per la simeprevir.
Effetti collaterali generali
-20%
| Effetti collaterali | ∑ frequenza | sim | ami |
|---|---|---|---|
| Iperbilirubinemia | 66.0 % | 66.0 | n.a. |
| Nausea | 35.2 % | 17.5 | 21.5 |
| Fatica | 24.0 % | 24.0 | n.a. |
| Vomito | 21.5 % | n.a. | 21.5 |
| Mal di testa | 20.0 % | 20.0 | n.a. |
| Fotosensibilità | 11.2 % | 5.0 | 6.5 |
| Ipotiroidismo | 10.0 % | n.a. | 10.0 |
| Costipazione | 6.5 % | n.a. | 6.5 |
| Perdita di appetito | 6.5 % | n.a. | 6.5 |
| Atassia | 6.5 % | n.a. | 6.5 |
Estratto tabellare degli effetti collaterali più comuni
Segno (+): effetto collaterale descritto, ma frequenza non nota
Segno (↑/↓): frequenza piuttosto maggiore / minore a causa dell'esposizione
Segno (+): effetto collaterale descritto, ma frequenza non nota
Segno (↑/↓): frequenza piuttosto maggiore / minore a causa dell'esposizione
Neurologico
Problema di coordinamento (6.5%): amiodarone
Vertigini (6.5%): amiodarone
Parestesia (6.5%): amiodarone
Neuropatia periferica: amiodarone
Pseudotumor cerebri: amiodarone
Oftalmologico
Visione offuscata (6.5%): amiodarone
Neurite ottica: amiodarone
Perdita della vista: amiodarone
Endocrino
Ipertiroidismo (2%): amiodarone
Respiratorio
Sindrome da distress respiratorio acuto (2%): amiodarone
Fibrosi polmonare: amiodarone
Cardiaco
Ipotensione: amiodarone
Bradicardia: amiodarone
Insufficienza cardiaca: amiodarone
Aritmia ventricolare: amiodarone
Dermatologico
Eruzione cutanea: simeprevir
Sindrome di Stevens Johnson: amiodarone
Necrolisi epidermica tossica: amiodarone
Hematologico
Trombocitopenia: amiodarone
Hepatica
Epatotossicità: amiodarone
Insufficienza epatica: simeprevir
Immunologico
Reazione di ipersensibilità: amiodarone
Renale
Insufficienza renale: amiodarone
Vascolare
Vasculite: amiodarone
Limitazioni
Sulla base delle vostre
Riferimenti letterari
Authors: Middlekauff HR Stevenson WG Saxon LA Stevenson LW
Abstract: Amiodarone is considered to be safe in patients with prior QT prolongation and torsades de pointes taking class I antiarrhythmic agents who require continued antiarrhythmic drug therapy. However, the safety of amiodarone in advanced heart failure patients with a history of drug-induced torsades de pointes, who may be more susceptible to proarrhythmia, is unknown. Therefore, the objective of this study was to assess amiodarone safety and efficacy in heart failure patients with prior antiarrhythmic drug-induced torsades de pointes. We determined the history of torsades de pointes in 205 patients with heart failure treated with amiodarone, and compared the risk of sudden death in patients with and without such a history. To evaluate the possibility that all patients with a history of torsades de pointes would be at high risk for sudden death regardless of amiodarone treatment, we compared this risk in patients with a history of torsades de pointes who were and were not subsequently treated with amiodarone. Of 205 patients with advanced heart failure, 8 (4%) treated with amiodarone had prior drug-induced torsades de pointes. Despite similar severity of heart failure, the 1-year actuarial sudden death risk was markedly increased in amiodarone patients with than without prior torsades de pointes (55% vs 15%, p = 0.0001). Similarly, the incidence of 1-year sudden death was markedly increased in patients with prior torsades de pointes taking amiodarone compared with such patients who were not subsequently treated with amiodarone (55% vs 0%, p = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)
Pubmed Id: 7653452
Abstract: Amiodarone is considered to be safe in patients with prior QT prolongation and torsades de pointes taking class I antiarrhythmic agents who require continued antiarrhythmic drug therapy. However, the safety of amiodarone in advanced heart failure patients with a history of drug-induced torsades de pointes, who may be more susceptible to proarrhythmia, is unknown. Therefore, the objective of this study was to assess amiodarone safety and efficacy in heart failure patients with prior antiarrhythmic drug-induced torsades de pointes. We determined the history of torsades de pointes in 205 patients with heart failure treated with amiodarone, and compared the risk of sudden death in patients with and without such a history. To evaluate the possibility that all patients with a history of torsades de pointes would be at high risk for sudden death regardless of amiodarone treatment, we compared this risk in patients with a history of torsades de pointes who were and were not subsequently treated with amiodarone. Of 205 patients with advanced heart failure, 8 (4%) treated with amiodarone had prior drug-induced torsades de pointes. Despite similar severity of heart failure, the 1-year actuarial sudden death risk was markedly increased in amiodarone patients with than without prior torsades de pointes (55% vs 15%, p = 0.0001). Similarly, the incidence of 1-year sudden death was markedly increased in patients with prior torsades de pointes taking amiodarone compared with such patients who were not subsequently treated with amiodarone (55% vs 0%, p = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)
Authors: Ouwerkerk-Mahadevan S Snoeys J Peeters M Beumont-Mauviel M Simion A
Abstract: Simeprevir is an NS3/4A protease inhibitor approved for the treatment of hepatitis C infection, as a component of combination therapy. Simeprevir is metabolized by the cytochrome P450 (CYP) system, primarily CYP3A, and is a substrate for several drug transporters, including the organic anion transporting polypeptides (OATPs). It is susceptible to metabolic drug-drug interactions with drugs that are moderate or strong CYP3A inhibitors (e.g. ritonavir and erythromycin) or CYP3A inducers (e.g. rifampin and efavirenz); coadministration of these drugs may increase or decrease plasma concentrations of simeprevir, respectively, and should be avoided. Clinical studies have shown that simeprevir is a mild inhibitor of CYP1A2 and intestinal CYP3A but does not inhibit hepatic CYP3A. The effects of simeprevir on these enzymes are of clinical relevance only for narrow-therapeutic-index drugs that are metabolized solely by these enzymes (e.g. oral midazolam). Simeprevir does not have a clinically relevant effect on the pharmacokinetics of rilpivirine, tacrolimus, oral contraceptives and several other drugs metabolized by CYP enzymes. Simeprevir is a substrate and inhibitor of the transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and OATP1B1/3. Cyclosporine is an inhibitor of OATP1B1/3, BCRP and P-gp, and a mild inhibitor of CYP3A; cyclosporine causes a significant increase in simeprevir plasma concentrations, and coadministration is not recommended. Clinical studies have demonstrated increases in coadministered drug concentrations for drugs that are substrates of the OATP1B1/3, BRCP (e.g. rosuvastatin) and P-gp (e.g. digoxin) transporters; these drugs should be administered with dose titration and or/close monitoring.
Pubmed Id: 26353895
Abstract: Simeprevir is an NS3/4A protease inhibitor approved for the treatment of hepatitis C infection, as a component of combination therapy. Simeprevir is metabolized by the cytochrome P450 (CYP) system, primarily CYP3A, and is a substrate for several drug transporters, including the organic anion transporting polypeptides (OATPs). It is susceptible to metabolic drug-drug interactions with drugs that are moderate or strong CYP3A inhibitors (e.g. ritonavir and erythromycin) or CYP3A inducers (e.g. rifampin and efavirenz); coadministration of these drugs may increase or decrease plasma concentrations of simeprevir, respectively, and should be avoided. Clinical studies have shown that simeprevir is a mild inhibitor of CYP1A2 and intestinal CYP3A but does not inhibit hepatic CYP3A. The effects of simeprevir on these enzymes are of clinical relevance only for narrow-therapeutic-index drugs that are metabolized solely by these enzymes (e.g. oral midazolam). Simeprevir does not have a clinically relevant effect on the pharmacokinetics of rilpivirine, tacrolimus, oral contraceptives and several other drugs metabolized by CYP enzymes. Simeprevir is a substrate and inhibitor of the transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and OATP1B1/3. Cyclosporine is an inhibitor of OATP1B1/3, BCRP and P-gp, and a mild inhibitor of CYP3A; cyclosporine causes a significant increase in simeprevir plasma concentrations, and coadministration is not recommended. Clinical studies have demonstrated increases in coadministered drug concentrations for drugs that are substrates of the OATP1B1/3, BRCP (e.g. rosuvastatin) and P-gp (e.g. digoxin) transporters; these drugs should be administered with dose titration and or/close monitoring.
Authors: Ivanyuk A Livio F Biollaz J Buclin T
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.
Pubmed Id: 28210973
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.
Authors: Etchegoyen CV Keller GA Mrad S Cheng S Di Girolamo G
Abstract: BACKGROUND: The most common acquired cause of Long QT syndrome (LQTS) is drug induced QT interval prolongation. It is an electrophysiological entity, which is characterized by an extended duration of the ventricular repolarization. Reflected as a prolonged QT interval in a surface ECG, this syndrome increases the risk for polymorphic ventricular tachycardia (Torsade de Pointes) and sudden death. METHOD: Bibliographic databases as MEDLINE and EMBASE, reports and drug alerts from several regulatory agencies (FDA, EMEA, ANMAT) and drug safety guides (ICH S7B, ICH E14) were consulted to prepare this article. The keywords used were: polymorphic ventricular tachycardia, adverse drug events, prolonged QT, arrhythmias, intensive care unit and Torsade de Pointes. Such research involved materials produced up to December 2017. RESULTS: Because of their mechanism of action, antiarrhythmic drugs such as amiodarone, sotalol, quinidine, procainamide, verapamil and diltiazem are associated to the prolongation of the QTc interval. For this reason, they require constant monitoring when administered. Other noncardiovascular drugs that are widely used in the Intensive Care Unit (ICU), such as ondansetron, macrolide and fluoroquinolone antibiotics, typical and atypical antipsychotics agents such as haloperidol, thioridazine, and sertindole are also frequently associated with the prolongation of the QTc interval. As a consequence, critical patients should be closely followed and evaluated. CONCLUSION: ICU patients are particularly prone to experience a QTc interval prolongation mainly for two reasons. In the first place, they are exposed to certain drugs that can prolong the repolarization phase, either by their mechanism of action or through the interaction with other drugs. In the second place, the risk factors for TdP are prevalent clinical conditions among critically ill patients. As a consequence, the attending physician is expected to perform preventive monitoring and ECG checks to control the QTc interval.
Pubmed Id: 29473523
Abstract: BACKGROUND: The most common acquired cause of Long QT syndrome (LQTS) is drug induced QT interval prolongation. It is an electrophysiological entity, which is characterized by an extended duration of the ventricular repolarization. Reflected as a prolonged QT interval in a surface ECG, this syndrome increases the risk for polymorphic ventricular tachycardia (Torsade de Pointes) and sudden death. METHOD: Bibliographic databases as MEDLINE and EMBASE, reports and drug alerts from several regulatory agencies (FDA, EMEA, ANMAT) and drug safety guides (ICH S7B, ICH E14) were consulted to prepare this article. The keywords used were: polymorphic ventricular tachycardia, adverse drug events, prolonged QT, arrhythmias, intensive care unit and Torsade de Pointes. Such research involved materials produced up to December 2017. RESULTS: Because of their mechanism of action, antiarrhythmic drugs such as amiodarone, sotalol, quinidine, procainamide, verapamil and diltiazem are associated to the prolongation of the QTc interval. For this reason, they require constant monitoring when administered. Other noncardiovascular drugs that are widely used in the Intensive Care Unit (ICU), such as ondansetron, macrolide and fluoroquinolone antibiotics, typical and atypical antipsychotics agents such as haloperidol, thioridazine, and sertindole are also frequently associated with the prolongation of the QTc interval. As a consequence, critical patients should be closely followed and evaluated. CONCLUSION: ICU patients are particularly prone to experience a QTc interval prolongation mainly for two reasons. In the first place, they are exposed to certain drugs that can prolong the repolarization phase, either by their mechanism of action or through the interaction with other drugs. In the second place, the risk factors for TdP are prevalent clinical conditions among critically ill patients. As a consequence, the attending physician is expected to perform preventive monitoring and ECG checks to control the QTc interval.
Authors: Yau S Chan P Sapkin J Hsieh E
Abstract: Amiodarone is one of the most commonly used antiarrhythmic drugs. Despite its well-known side effects, amiodarone is considered to be a relatively safe drug, especially in short-term usage to prevent life-threatening ventricular arrhythmias. Our case demonstrates an instance where short-term usage can yield drug side effect.
Pubmed Id: 30147903
Abstract: Amiodarone is one of the most commonly used antiarrhythmic drugs. Despite its well-known side effects, amiodarone is considered to be a relatively safe drug, especially in short-term usage to prevent life-threatening ventricular arrhythmias. Our case demonstrates an instance where short-term usage can yield drug side effect.
