Avvisi di avvertenza
Estensione di tempo QT
Effetti avversi del farmaco
|Mal di testa|
Varianti ✨Per la valutazione computazionalmente intensiva delle varianti, scegli l'abbonamento standard a pagamento.
Aree di applicazione
Spiegazioni per i pazienti
Avvisi di avvertenza
Non abbiamo ulteriori avvertenze per la combinazione di alogliptin, fluconazolo e ketoconazolo. Si prega di consultare anche le informazioni specialistiche pertinenti.
I cambiamenti nell'esposizione menzionati si riferiscono ai cambiamenti nella curva concentrazione plasmatica-tempo [AUC]. L'esposizione alla ketoconazolo aumenta al 147%, se combinato con alogliptin (100%) e fluconazolo (147%). L'esposizione alla alogliptin aumenta al 107%, se combinato con fluconazolo (106%) e ketoconazolo (107%). Non ci aspettiamo alcun cambiamento nell'esposizione alla fluconazolo, se combinato con alogliptin (100%) e ketoconazolo (100%).
I parametri farmacocinetici della popolazione media sono utilizzati come punto di partenza per il calcolo delle singole variazioni di esposizione dovute alle interazioni.
La alogliptin ha un'elevata biodisponibilità orale [ F ] del 95%, motivo per cui i livelli plasmatici massimi [Cmax] tendono a cambiare poco durante un'interazione. L'emivita terminale [ t12 ] è di 21 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti dopo circa 84 ore. Il legame proteico [ Pb ] è molto debole al 20% e il volume di distribuzione [ Vd ] è molto grande a 417 litri. Poiché la sostanza ha una bassa velocità di estrazione epatica di 0,9, lo spostamento dal legame proteico [Pb] nel contesto di un'interazione può aumentare l'esposizione. Circa il 65.5% di una dose somministrata viene escreta immodificata attraverso i reni e questa proporzione è raramente modificata dalle interazioni. Il metabolismo avviene tramite CYP2D6 e CYP3A4, tra gli altri.
La fluconazolo ha un'elevata biodisponibilità orale [ F ] del 90%, motivo per cui i livelli plasmatici massimi [Cmax] tendono a cambiare poco durante un'interazione. L'emivita terminale [ t12 ] è piuttosto lunga a 30 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti solo dopo più di 120 ore. Il legame proteico [ Pb ] è molto debole al 11.5% e il volume di distribuzione [ Vd ] è di 56 litri. Circa il 80.0% di una dose somministrata viene escreta immodificata attraverso i reni e questa proporzione è raramente modificata dalle interazioni. Il metabolismo non avviene tramite i comuni citocromi.
La ketoconazolo ha una biodisponibilità orale media [ F ] del 67%, motivo per cui i livelli plasmatici massimi [Cmax] tendono a cambiare con un'interazione. L'emivita terminale [ t12 ] è piuttosto breve a 5 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti rapidamente. Il legame proteico [ Pb ] è moderatamente forte al 91.5% e il volume di distribuzione [ Vd ] è molto grande a 84 litri, Poiché la sostanza ha una bassa velocità di estrazione epatica di 0,9, lo spostamento dal legame proteico [Pb] nel contesto di un'interazione può aumentare l'esposizione. Il metabolismo avviene principalmente tramite CYP3A4 e il trasporto attivo avviene in particolare tramite PGP.
|Effetti serotoninergici a||0||Ø||Ø||Ø|
Valutazione: Secondo le nostre conoscenze, né la alogliptin, fluconazolo né la ketoconazolo aumentano l'attività serotoninergica.
|Kiesel & Durán b||0||Ø||Ø||Ø|
Valutazione: Secondo i nostri risultati, né la alogliptin, fluconazolo né la ketoconazolo aumentano l'attività anticolinergica.
Estensione di tempo QT
Valutazione: In combinazione, fluconazolo e ketoconazolo possono potenzialmente innescare aritmie ventricolari di tipo torsione di punta. Non conosciamo alcun potenziale di prolungamento dell'intervallo QT per la alogliptin.
Effetti collaterali generali
|Effetti collaterali||∑ frequenza||alo||flu||ket|
|Mal di testa||11.4 %||4.3||7.5||n.a.|
|Infezione delle vie respiratorie superiori||4.5 %||4.5||n.a.||n.a.|
|Sensazione di bruciore||1.0 %||n.a.||n.a.||+|
|Eruzione cutanea||1.0 %||n.a.||n.a.||+|
|Insufficienza surrenalica||1.0 %||n.a.||n.a.||+|
Fosfatasi alcalina aumentata: fluconazolo
ALT aumentata: fluconazolo
AST aumentata: fluconazolo
Insufficienza epatica: alogliptin, fluconazolo
Epatotossicità: ketoconazolo, fluconazolo
Reazione di ipersensibilità: alogliptin, ketoconazolo
Sindrome DRESS: fluconazolo
Insufficienza cardiaca: alogliptin
Aritmia ventricolare: ketoconazolo
Sindrome di Stevens Johnson: alogliptin, fluconazolo
Necrolisi epidermica tossica: fluconazolo
Sulla base delle vostre
Abstract: 1. The oral pharmacokinetics of fluconazole were studied in three groups of volunteers (n = 5) with various degrees of renal function (GFR greater than 70 ml min-1; 20-70 ml min-1; less than 20 ml min-1) and in a group of patients with chronic end-stage renal failure requiring regular haemodialysis. 2. The pharmacokinetics of fluconazole were markedly affected by impaired renal function with the elimination of half-life in Group III (GFR less than 20 ml min-1) being approximately three times that observed in normal volunteers (Group I). 3. Fluconazole renal clearance was positively correlated with GFR. 4. Non-renal clearance of fluconazole decreased with decreasing renal function. 5. Approximately 38% of the 50 mg dose of fluconazole was removed by haemodialysis extending over a 3 h period.
Abstract: A 25-year-old woman who was hospitalized for worsening endocarditis had a prolonged QT interval at baseline and developed monomorphic ventricular arrhythmias, which were managed successfully with pacing and antiarrhythmic therapy. Several days later, the patient started receiving high-dose fluconazole for fungemia and subsequently experienced episodes of torsades de pointes, a polymorphic ventricular arrhythmia associated with a prolonged QT interval or prominent U wave on the electrocardiogram. The arrhythmia developed in the presence of known risk factors. Clinicians should be aware of these risk factors and other relevant structural similarities with drugs that cause torsades de pointes so that they can recognize patients who may be at risk for fluconazole-associated arrhythmia.
Abstract: Ketoconazole is not known to be proarrhythmic without concomitant use of QT interval-prolonging drugs. We report a woman with coronary artery disease who developed a markedly prolonged QT interval and torsades de pointes (TdP) after taking ketoconazole for treatment of fungal infection. Her QT interval returned to normal upon withdrawal of ketoconazole. Genetic study did not find any mutation in her genes that encode cardiac IKr channel proteins. We postulate that by virtue of its direct blocking action on IKr, ketoconazole alone may prolong QT interval and induce TdP. This calls for attention when ketoconazole is administered to patients with risk factors for acquired long QT syndrome.
Abstract: OBJECTIVE: To investigate the effect of efavirenz on the ketoconazole pharmacokinetics in HIV-infected patients. METHODS: Twelve HIV-infected patients were assigned into a one-sequence, two-period pharmacokinetic interaction study. In phase one, the patients received 400 mg of ketoconazole as a single oral dose on day 1; in phase two, they received 600 mg of efavirenz once daily in combination with 150 mg of lamivudine and 30 or 40 mg of stavudine twice daily on days 2 to 16. On day 16, 400 mg of ketoconazole was added to the regimen as a single oral dose. Ketoconazole pharmacokinetics were studied on days 1 and 16. RESULTS: Pretreatment with efavirenz significantly increased the clearance of ketoconazole by 201%. C(max) and AUC(0-24) were significantly decreased by 44 and 72%, respectively. The T ((1/2)) was significantly shorter by 58%. CONCLUSION: Efavirenz has a strong inducing effect on the metabolism of ketoconazole.
Abstract: Fluconazole is an antifungal medication that has been reported to cause prolongation of the QT interval and Torsades de Pointes (TdP) ventricular tachycardia in adults. We describe the case of an 11-year-old child treated with fluconazole who developed ventricular arrhythmia culminating in TdP. We discuss the possible roles played by genetic and environmental factors in this child's rhythm disturbances. After briefly summarizing similar cases from the adult literature, we outline the putative mechanism by which fluconazole may cause arrhythmia. This case should alert pediatricians to the possible risks of fluconazole use, especially in the presence of electrolyte abnormalities, diuretic use, therapy with other pro-arrhythmic agents, or suspicion of congenital Long-QT Syndrome.
Abstract: PURPOSE: A case of torsades de pointes associated with fluconazole use is described. SUMMARY: A 68-year-old woman with a history of hypertension treated with 2.5 mg of indapamide for 16 months sought medical treatment after having two falls 1 month apart. A computed tomography scan and subsequent magnetic resonance imaging of the brain revealed a lesion in the left pons and middle cerebellar peduncle. Biopsy of the pontine lesion revealed large yeast forms and subsequently revealed Cryptococcus neoformans var. gattii. The patient was initially treated with conventional amphotericin B and flucytosine for six weeks. The first week of therapy was complicated by hypokalemia, hypomagnesemia, and an episode of atrial fibrillation that was managed with electrolyte replacement, commencement of metoprolol, and switching from conventional amphotericin B to amphotericin B lipid complex. After six weeks, liposomal amphotericin was discontinued and high-dose oral fluconazole was initiated. Six days after beginning fluconazole therapy, the patient had a generalized tonic-clonic seizure and suffered cardiopulmonary arrest. Postresuscitation, an electrocardiogram demonstrated a corrected Q-T interval of 556 msec. Recurrent episodes of torsades de pointes were also recorded postarrest. Fluconazole was discontinued at this time, and liposomal amphotericin B was resumed. Neurologic and electroencephalographic assessment conducted 48 hours postarrest revealed that significant neurologic damage had been sustained. Supportive care was withdrawn, and the patient died two days later. A postmortem examination revealed no coronary artery disease or hemorrhagic transformation of the pontine cryptococcoma. CONCLUSION: Treatment with high-dose fluconazole was the probable cause of torsades de pointes in a patient with risk factors for this condition. The benefits and risks of using fluconazole should be carefully weighed for patients with risk factors for Q-T interval prolongation.
Abstract: AIMS: To investigate the interaction between ketoconazole and darunavir (alone and in combination with low-dose ritonavir), in HIV-healthy volunteers. METHODS: Volunteers received darunavir 400 mg bid and darunavir 400 mg bid plus ketoconazole 200 mg bid, in two sessions (Panel 1), or darunavir/ritonavir 400/100 mg bid, ketoconazole 200 mg bid and darunavir/ritonavir 400/100 mg bid plus ketoconazole 200 mg bid, over three sessions (Panel 2). Treatments were administered with food for 6 days. Steady-state pharmacokinetics following the morning dose on day 7 were compared between treatments. Short-term safety and tolerability were assessed. RESULTS: Based on least square means ratios (90% confidence intervals), during darunavir and ketoconazole co-administration, darunavir area under the curve (AUC(12h)), maximum plasma concentration (C(max)) and minimum plasma concentration (C(min)) increased by 155% (80, 261), 78% (28, 147) and 179% (58, 393), respectively, compared with treatment with darunavir alone. Darunavir AUC(12h), C(max) and C(min) increased by 42% (23, 65), 21% (4, 40) and 73% (39, 114), respectively, during darunavir/ritonavir and ketoconazole co-administration, relative to darunavir/ritonavir treatment. Ketoconazole pharmacokinetics was unchanged by co-administration with darunavir alone. Ketoconazole AUC(12h), C(max) and C(min) increased by 212% (165, 268), 111% (81, 144) and 868% (544, 1355), respectively, during co-administration with darunavir/ritonavir compared with ketoconazole alone. CONCLUSIONS: The increase in darunavir exposure by ketoconazole was lower than that observed previously with ritonavir. A maximum ketoconazole dose of 200 mg day(-1) is recommended if used concomitantly with darunavir/ritonavir, with no dose adjustments for darunavir/ritonavir.
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.
Abstract: All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies.
Abstract: A biowaiver is accepted by the Brazilian Health Surveillance Agency (ANVISA) for immediate-release solid oral products containing Biopharmaceutics Classification System (BCS) class I drugs showing rapid drug dissolution. This study aimed to simulate plasma concentrations of fluconazole capsules with different dissolution profiles and run population simulation to evaluate their bioequivalence. The dissolution profiles of two batches of the reference product Zoltec150 mg capsules, A1 and A2, and two batches of other products (B1 and B2; C1 and C2), as well as plasma concentration-time data of the reference product from the literature, were used for the simulations. Although products C1 and C2 had drug dissolutions < 85% in 30 min at 0.1 M HCl, simulation results demonstrated that these products would show the same in vivo performance as products A1, A2, B1, and B2. Population simulation results of the ln-transformed 90% confidence interval for the ratio ofand AUCvalues for all products were within the 80-125% interval, showing to be bioequivalent. Thus, even though the in vitro dissolution behavior of products C1 and C2 was not equivalent to a rapid dissolution profile, the computer simulations proved to be an important tool to show the possibility of bioequivalence for these products.