What evidence exists regarding ifosfamide induced heart failure, and hyponatremia/Syndrome of Inapp

Fråga: What evidence exists regarding ifosfamide induced heart failure, and hyponatremia/Syndrome of Inappropriate Anti Diuretic Hormone secretion (SIADH)? Is CYP genotyping relevant to possibly elucidate the pharmacological background for this reaction?

The question concerns a 66-year-old woman with a medical history of hypertension and a lymphoma that had been treated with recurrent combinations of immunosuppressors. The patient had thus received a CHOP chemotherapeutic treatment in February and then suffered from an asymptomatic, temporary decrease in left ventricular ejection fraction (LVEF). The patient underwent an echocardiography that showed a LVEF of 50 %, preceding another chemotherapeutic treatment with a combination of methotrexate, ifosfamide, mitoguazone and etoposide (MIME). The first regime included daily doses of 1700 mg ifosfamide (1000 mg/m2). Thereafter the patient rapidly developed symptoms of a combined right and left ventricular heart failure with dyspnoea, weight gain and pretibial oedema. The MIME regime was inhibited five days later and another echocardiography the same date showed an ejection fraction of 20 %. Sodium had decreased from 129 mM to 120 mM and also potassium was low. S-Creatinine stayed normal during the whole course of events. Radiological examination showed pleural effusion. The patient was prescribed fluid intravenously, loop diuretics, bisoprolol (Emconcor), and enalapril. Her condition improved clinically during the following days loosing 12 kilos of weight and being less dyspnoeic. The electrolyte disturbances were normalised.

Other medications included except for paracetamol, allopurinol, diazepam and oxycodone, also fluconazole and meropenem.

Sammanfattning: Congestive heart failure is a well-documented dose related adverse effect. The mechanism is unknown. The doses associated with cardiotoxicity are usually much higher than those used in the current regime why it indeed is relevant to consider the reasons for this reaction in this particular patient. The patient may have had an incipient cardiac failure making her more vulnerable. Fluconazole that is a known inhibitor of CYP3A4 may have increased the exposure for ifosfamide and thereby contributed to the reaction. However, as there are no known clinically relevant polymorphisms in the gene coding for CYP3A4, CYP genotyping will not give any further information. Although well recognised, SIADH occurs only infrequently with an incidence of less then 0.1%, and does not seem to be dose related.

Svar: Ifosfamide is an oxazaphosphorine analog of cyclophosphamide with an alkylating activity. Ifosfamide is extensively metabolised in the liver in a dose related manner. At high doses (over 3.8 g/m2), only 50% is metabolised, compared to 80% at doses less than 3 g/m2. The proportion excreted by the kidney also varies with doses in a reversed manner. At low doses, between 12 and 18% is excreted renally while the corresponding figures range from 70% to 86% at high doses (1). Metabolic activation occurs by way of 4-hydroxylation primarily catalysed by CYP3A4. A second metabolic reaction of importance appears to be side chain oxidation. This N-dechloroethylation pathway, also catalysed by CYP3A4 produces chloroacetaldehyde, a potential neurotoxin. (2).

The cardiotoxicity of ifosfamide and cyclophosphamide is well documented, as they are known to cause severe cardiac dysfunction, including congestive heart failure, in a dose related manner (3,4,5). One study states that the dose that has caused myocardial injury usually has been "far in excess of 1000 mg/m2" (3). No definite risk estimation exists, but Goldberg et al describe 84 pediatric patients who received 50mg/kg/day for four days as a preparation for marrow grafting. Fourteen patients (17%) had symptoms and signs of cardiotoxicity within ten days and six patients died. Earlier studies reviewed by Goldberg et al in the same paper imply an incidence of symptomatic cardiomyopathy of 22% (5). The mechanism of cardiotoxicity is unknown.

The doses associated with cardiotoxicity are usually much higher than those used in the current regime why it is relevant to consider the possible reasons for this reaction in this particular patient. The medical history with hypertension, a temporary decrease in left ventricular ejection fraction following CHOP treatment and a persistent LVEF in the lower range of what is considered normal, implies an incipient cardiac failure. Fluconazole prescribed to the patient for some days before the initiation of the cytostatic regime is a known inhibitor of CYP3A4 and is therefore likely to interact with the metabolism of ifosfamide. However, as the exact mediator of the cardiotoxicity is unknown it is not possible to say whether co-administration of fluconazole really does increase the risk or not. One study however, shows that fluconazole reduces cyclophosphamide clearance by approximately 50 % (2). Concerning the relevance of CYP genotyping, there are no known clinically relevant polymorphisms in the gene coding for CYP3A4.

Although well recognised, Syndrome of Inappropriate Anti Diuretic Hormone secretion (SIADH) occurs only infrequently with an incidence of less then 0.1%, and does not seem to be dose related (1).

We recommend this case to be reported to the regional adverse reaction monitoring centre. Ifosfamide. Drugdex(R) System; Thomson MICROMEDEX, Greenwood Village, Colorado (cited 2006-07-17) Levy RH, Thummel KE, Trager WF, Hansten PD, Eichelbaum M. Metabolic drug interactions. Philadelphia: Williams & Wilkins; 2000 Klastersky J. Side effects of ifosfamide. Oncology. 2003;65(suppl 2):7-10. Floyd JD, Nguyen DT, Lobins RL, Bashir Q, Doll DC, Perry MC. Cardiotoxicity of cancer therapy. J Clin Oncol. 2005;23:7685-96. Goldberg MA, Antin JH, Guinan EC, Rappeport JM. Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor. Blood. 1986;68;1114-8.