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Pharmacokinetic interaction between taxanes and amiodarone leading to severe toxicity.

ABSTRACT: ADVERSE EVENT:A drug interaction leading to severe skin and mucosal toxicity. DRUGS IMPLICATED:Paclitaxel, docetaxel and amiodarone. THE PATIENT:A 77-year-old woman with a history of hypertension, hyperlipidemia, and palpitations, managed with amiodarone, was treated for HER2-positive invasive ductal breast cancer with paclitaxel and trastuzumab as an adjunct to surgery. EVIDENCE THAT LINKS THE DRUG TO THE EVENT:There was a strong temporal relationship between the taxane therapy and the development of severe skin and mucosal toxicity due to an unexpected reduction in taxane clearance. MANAGEMENT:Initially, conversion of paclitaxel to docetaxel, then cessation of docetaxel, symptomatic treatment, rehydration and placement of a nasogastric tube. MECHANISM:Increased exposure to paclitaxel and subsequently docetaxel due to interaction with amiodarone was suspected and confirmed on pharmacokinetic sampling. Analysis of two blood samples taken 9 and 10 days after docetaxel revealed plasma levels of 4.73 and 4.09 ng ml-1 , respectively, leading to a 79% decreased individual (Bayesian maximum a posteriori) clearance estimate of 9.15 l h-1 , corresponding to an estimated fivefold increase in AUC. Paclitaxel was also present in these samples (20 and 21 days after the last administration). IMPLICATIONS FOR THERAPY:Amiodarone inhibits cytochrome P450 (CYP) isoforms 2C8 and 3A4 as well as P-glycoprotein (P-gp) for which taxanes are substrates. However, interactions with amiodarone are not specified in the prescribing information. Clinicians should be aware of this interaction, particularly in an ageing population, where more patients requiring taxanes may already be receiving amiodarone for a comorbid cardiac condition.

SUBMITTER: Hammann F

PROVIDER: S-EPMC5346859 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Pharmacokinetic interaction between taxanes and amiodarone leading to severe toxicity.

Hammann Felix F Gotta Verena V Conen Katrin K Medinger Michael M Cesana Philipp P Rochlitz Christoph C Taegtmeyer Anne B AB

British journal of clinical pharmacology 20161120 4

<h4>Adverse event</h4>A drug interaction leading to severe skin and mucosal toxicity.<h4>Drugs implicated</h4>Paclitaxel, docetaxel and amiodarone.<h4>The patient</h4>A 77-year-old woman with a history of hypertension, hyperlipidemia, and palpitations, managed with amiodarone, was treated for HER2-positive invasive ductal breast cancer with paclitaxel and trastuzumab as an adjunct to surgery.<h4>Evidence that links the drug to the event</h4>There was a strong temporal relationship between the ta ...[more]

PMID: 27868228

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Project description:INTRODUCTION:Amiodarone is often used in the suppression of tachyarrhythmias. One of the more serious adverse effects includes amiodarone pulmonary toxicity (APT). Several pulmonary diseases can manifest including interstitial pneumonitis, organizing pneumonia, acute respiratory distress syndrome, diffuse alveolar hemorrhage, pulmonary nodules or masses, and pleural effusion. Incidence of APT varies from 5-15% and is correlated to dosage, age of the patient, and preexisting lung disease. DESCRIPTION:A 56-year-old male with a past medical history of coronary artery disease and chronic obstructive pulmonary disease was admitted for a coronary artery bypass graft. Post-operatively, the patient was admitted to the ICU for ventilator management and continued to receive his home dose of amiodarone 400 mg orally twice daily, which he had been taking for the past 3 months. The patient was found to be hypoxemic with a PaO2 52 mmHg and bilateral infiltrates on chest x-ray. Patient also complained of new onset dyspnea. Physical exam found bilateral rhonchi with bibasilar crackles and subcutaneous emphysema along the left anterior chest wall. Daily chest x-rays showed worsening of bilateral interstitial infiltrates and pleural effusions. A chest high-resolution computed tomography on post-operative day 3 showed extensive and severe bilateral ground glass opacities. APT was suspected and amiodarone was discontinued. A course of oral prednisone without antibiotics was initiated, and after one week of treatment the chest film cleared, the PaO2 value normalized and dyspnea resolved. DISCUSSION:APT occurs via cytotoxic T cells and indirectly by immunological reaction. Typically the lungs manifest a diffuse interstitial pneumonitis with varying degrees of fibrosis. Infiltrates with a 'ground-glass' appearance appreciated on HRCT are more definitive than chest x-ray. Pulmonary nodules can be seen, frequently in the upper lobes. These are postulated to be accumulations of amiodarone in areas of previous inflammation. Those undergoing major cardiothoracic surgery are known to be predisposed to APT. Some elements require consideration: a baseline pulmonary function test (PFT) did not exist prior. APT would manifest a restrictive pattern of PFTs. In APT diffusing capacity (DLCO) is generally >20 percent from baseline. A DLCO was not done in this patient. Therefore, not every type of interstitial lung disease could be ruled out. Key features support a clinical diagnosis: (1) new dyspnea, (2) exclusion of lung infection, (3) exclusion of heart failure, (4) new radiographic features, (5) improvement with withdrawal of amiodarone. Our case illustrates consideration of APT in patients who have extensive use of amiodarone and new onset dyspnea.

Project description:BACKGROUND AND PURPOSE: Amiodarone (2-n-butyl-3-[3,5 diiodo-4-diethylaminoethoxybenzoyl]-benzofuran, B2-O-CH(2)CH(2)-N-diethyl) is an effective class III antiarrhythmic drug demonstrating potentially life-threatening organ toxicity. The principal aim of the study was to find amiodarone analogues that retained human ether-a-go-go-related protein (hERG) channel inhibition but with reduced cytotoxicity. EXPERIMENTAL APPROACH: We synthesized amiodarone analogues with or without a positively ionizable nitrogen in the phenolic side chain. The cytotoxic properties of the compounds were evaluated using HepG2 (a hepatocyte cell line) and A549 cells (a pneumocyte line). Interactions of all compounds with the hERG channel were measured using pharmacological and in silico methods. KEY RESULTS: Compared with amiodarone, which displayed only a weak cytotoxicity, the mono- and bis-desethylated metabolites, the further degraded alcohol (B2-O-CH(2)-CH(2)-OH), the corresponding acid (B2-O-CH(2)-COOH) and, finally, the newly synthesized B2-O-CH(2)-CH(2)-N-pyrrolidine were equally or more toxic. Conversely, structural analogues such as the B2-O-CH(2)-CH(2)-N-diisopropyl and the B2-O-CH(2)-CH(2)-N-piperidine were significantly less toxic than amiodarone. Cytotoxicity was associated with a drop in the mitochondrial membrane potential, suggesting mitochondrial involvement. Pharmacological and in silico investigations concerning the interactions of these compounds with the hERG channel revealed that compounds carrying a basic nitrogen in the side chain display a much higher affinity than those lacking such a group. Specifically, B2-O-CH(2)-CH(2)-N-piperidine and B2-O-CH(2)-CH(2)-N-pyrrolidine revealed a higher affinity towards hERG channels than amiodarone. CONCLUSIONS AND IMPLICATIONS: Amiodarone analogues with better hERG channel inhibition and cytotoxicity profiles than the parent compound have been identified, demonstrating that cytotoxicity and hERG channel interaction are mechanistically distinct and separable properties of the compounds.

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Pharmacokinetic interaction between taxanes and amiodarone leading to severe toxicity.

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Pharmacokinetic interaction between taxanes and amiodarone leading to severe toxicity.

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