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 abiraterone and atazanavir. Please also consult the relevant specialist information.
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. We did not detect any change in exposure to abiraterone. We currently cannot estimate the influence of atazanavir. We did not detect any change in exposure to atazanavir. We currently cannot estimate the influence of abiraterone.
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Abiraterone has a mean oral bioavailability [ F ] of 50%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is 18 hours and constant plasma levels [ Css ] are reached after approximately 72 hours. The protein binding [ Pb ] is very strong at 99.8% and the volume of distribution [ Vd ] is very large at 2815 liters, The metabolism mainly takes place via CYP3A4.
Atazanavir has a mean oral bioavailability [ F ] of 68%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is 6.5 hours and constant plasma levels [ Css ] are reached after approximately 26 hours. The protein binding [ Pb ] is moderately strong at 86%. The metabolism mainly takes place via CYP3A4 and the active transport takes place in particular via PGP.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither abiraterone nor atazanavir increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our knowledge, neither abiraterone nor atazanavir increase anticholinergic activity.
QT time prolongation
Rating: In combination, abiraterone and atazanavir can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||abi||ata|
|Peripheral edema||20.0 %||20.0||n.a.|
|Elevated ALT||18.2 %||13.0||6.0|
|Elevated AST||13.0 %||13.0||n.a.|
|Urinary tract infection||10.0 %||10.0||n.a.|
|Atrioventricular block||5.5 %||n.a.||5.5|
Rash (5%): atazanavir
Erythema multiforme: atazanavir
Stevens johnson syndrome: atazanavir
Neutropenia (5%): atazanavir
Abdominal pain (4%): atazanavir
Vomiting (3.5%): atazanavir
Myalgia (4%): atazanavir
Headache (3.5%): atazanavir
Atrial fibrillation (2.6%): abiraterone
Angina pectoris (1.6%): abiraterone
Fever (2%): atazanavir
Cholelithiasis (1.4%): atazanavir
Diabetes mellitus: atazanavir
Hypersensitivity reaction: atazanavir
Immune reconstitution syndrome: atazanavir
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: No Abstract available
Abstract: BACKGROUND: Atazanavir (ATV), an HIV protease inhibitor (PI) that may be preferred for the treatment of HIV-infected patients with cardiovascular comorbidities because of its favourable effects on plasma lipids, has been associated with cardiac rhythm disturbances. OBJECTIVE: To quantify the effect of ATV on corrected QT (QTc) and QTc dispersion (QTd), markers of the potential for cardiac dysrhythmia, in patients switching from other PIs to ATV. METHODS: In this prospective, single-centre, open-label study, 12-lead electrocardiograms were performed for subjects at baseline, 2 h after the first dose of ATV, and 1 month after initiation of ATV. RESULTS: Twenty-one patients (19 received ritonavir-boosted ATV) completed the study. There was a trend towards an increase in the QTc at 2 h after the first dose [mean+/-standard deviation 3.19+/-8.0 ms; 95% confidence interval (CI) -0.47 to 6.85 ms; P=0.084]. There was no difference between QTc values at baseline and at 1 month (-1.5+/-8.75 ms; 95% CI -5.50 to 2.46; P=0.43). There was a nonsignificant decrease in the QTd between baseline and 2 h (-5.1+/-15.19 ms; 95% CI -13.22 to 2.96; P=0.197) and between baseline and 1 month (-0.61+/-15.04 ms; 95% CI -8.1 to 6.87; P=0.865). A significant increase in the PR interval (7.4+/-10.7 ms; 95% CI 2.5 to 12.25 ms; P=0.005) was observed at 1 month. CONCLUSIONS: The use of ATV did not result in increases in the QTc interval or QTd. However, PR interval monitoring may be warranted in patients with underlying heart block or those treated with atrioventricular nodal blocking agents.
Abstract: We report, to our knowledge, the first documented case of torsades de pointes associated with atazanavir therapy. This case serves to highlight the need to monitor patients receiving atazanavir therapy who have risk factors for QT interval prolongation, such as female sex, bradycardia, electrolyte abnormalities, congestive heart failure, and a baseline prolonged QT interval.
Abstract: We aimed to determine the prevalence of a prolonged QTc interval in HIV-infected patients and its related factors through an observational study of a cohort of asymptomatic HIV-infected outpatients. All patients underwent a standard 12-lead electrocardiogram and a transthoracic echocardiogram. Prolonged QTc was considered if it was >440 ms in men and >450 ms in women. Epidemiological, clinical, and laboratory data were collected and the patients completed a questionnaire about cardiovascular risk factors. The analysis of the potential risk factors for prolonged QTc was done by multivariate logistic regression. The study included 194 patients, 84% men, with a mean age of 46.3 years. The mean duration of HIV infection was 122.6 months and 27.8% had AIDS. Antiretroviral therapy was being taken by 185 (96.4%) patients, and 92.4% of them had an undetectable viral load. The mean CD4 lymphocyte count was 553/mm(3). A total of 24 (12.4%) patients had a prolonged QTc interval, with a mean QTc of 456 ms. The factors associated with a prolonged QTc were hyperlipidemia (OR 3.7, 95% CI: 1.3-10.3; p=0.01) and diastolic dysfunction (OR 6.7, 95% CI: 2.4-18.3; p=0.0001), while the use of atazanavir was associated with a lower likelihood of having a prolonged QTc (OR 0.11, 95% CI: 0.02-0.5; p=0.008). A prolonged QTc syndrome was not uncommon in this cohort of asymptomatic HIV-infected patients with good immunovirological control. It was associated with hyperlipidemia and diastolic dysfunction. The use of atazanavir, compared with other protease inhibitors, was associated with a lower likelihood of having a prolonged QTc.
Abstract: Three open-label, single-dose studies investigated the impact of hepatic or renal impairment on abiraterone acetate pharmacokinetics and safety/tolerability in non-cancer patients. Patients (n = 8 each group) with mild/moderate hepatic impairment or end-stage renal disease (ESRD), and age-, BMI-matched healthy controls received a single oral 1,000 mg abiraterone acetate (tablet dose); while patients (n = 8 each) with severe hepatic impairment and matched healthy controls received 125- and 2,000-mg abiraterone acetate (suspension doses), respectively (systemic exposure of abiraterone acetate suspension is approximately half to that of tablet formulation). Blood was sampled at specified timepoints up to 72 or 96 hours postdose to measure plasma abiraterone concentrations. Abiraterone exposure was comparable between healthy controls and patients with mild hepatic impairment or ESRD, but increased by 4-fold in patients with moderate hepatic impairment. Despite a 16-fold reduction in dose, abiraterone exposure in patients with severe hepatic impairment was about 22% and 44% of the Cmax and AUC∞ of healthy controls, respectively. These results suggest that abiraterone pharmacokinetics were not changed markedly in patients with ESRD or mild hepatic impairment. However, the capacity to eliminate abiraterone was substantially compromised in patients with moderate or severe hepatic impairment. A single-dose administration of abiraterone acetate was well-tolerated.
Abstract: Two novel oral drugs that target androgen signaling have recently become available for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Abiraterone acetate inhibits the synthesis of the natural ligands of the androgen receptor, whereas enzalutamide directly inhibits the androgen receptor by several mechanisms. Abiraterone acetate and enzalutamide appear to be equally effective for patients with mCRPC pre- and postchemotherapy. Rational decision making for either one of these drugs is therefore potentially driven by individual patient characteristics. In this review, an overview of the pharmacokinetic characteristics is given for both drugs and potential and proven drug-drug interactions are presented. Additionally, the effect of patient-related factors on drug disposition are summarized and the limited data on the exposure-response relationships are described. The most important pharmacological feature of enzalutamide that needs to be recognized is its capacity to induce several key enzymes in drug metabolism. The potency to cause drug-drug interactions needs to be addressed in patients who are treated with multiple drugs simultaneously. Abiraterone has a much smaller drug-drug interaction potential; however, it is poorly absorbed, which is affected by food intake, and a large interpatient variability in drug exposure is observed. Dose reductions of abiraterone or, alternatively, the selection of enzalutamide, should be considered in patients with hepatic dysfunction. Understanding the pharmacological characteristics and challenges of both drugs could facilitate decision making for either one of the drugs.
Abstract: We present a case of a 77 year-old gentleman with previous coronary artery bypass grafting, admitted to hospital with recurrent torsades de pointes (TdP) due to abiraterone-induced hypokalaemia and prolonged QTc. The patient was on abiraterone and prednisone for metastatic prostate cancer. He required multiple defibrillations for recurrent TdP. Abiraterone is a relatively novel drug used in metastatic prostate cancer and we discuss this potential adverse effect and its management in this unusual presentation.
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.