Rhabdomyolysis from cytochrome p-450 interaction of ketoconazole and simvastatin in prostate cancer. (2003)

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are largely metabolized through the cytochrome P-450 oxidoreductases, with particular involvement of the 3A4 isotype.1 Individuals with diminished activity or pharmacological inhibition of this isotype are at particular risk for experiencing toxicities.1, 2 Ketoconazole has become a standard treatment for patients with prostate cancer who have progression on antiandrogen therapy. Because of the common metabolic pathways of ketoconazole and statin disposition, the potential exists for important drug interactions. CASE REPORT An active 73-year-old male with metastatic prostate cancer and a long-standing history of hypercholesterolemia had been treated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) medications for 8 years. Progressive prostatic cancer developed while the patient was receiving leuprolide and bicalutamide, and treatment was subsequently switched to leuprolide plus ketoconazole and hydrocortisone. Eleven days after beginning the new treatment the patient began to experience progressive proximal muscle weakness in the arms and legs without neuropathic symptoms or myalgia, and became bedridden. At presentation he had profound global muscle weakness affecting proximal more than distal muscles, and the legs more than the arms. Muscle tone, sensory examination and cranial nerves were normal, and the patient was not hyperreflexic. Magnetic resonance imaging demonstrated no new osseous lesions or cord compression. Plasma creatine kinase and aspartate aminotransferase values were massively increased, and electromyography showed acute diffuse noninflammatory myopathy (figs. 1 and 2). Medications were stopped, creatine kinase and aminotransferase levels gradually returned to normal and the patient improved for the next several days. When he was discharged home at the end of 2 weeks, he had not yet recovered full strength in the extremities. One month after discharge home the patient was ambulating comfortably. DISCUSSION One of the known side effects of statin therapy is dose related myopathy. Rhabdomyolysis may be severe but is rare. Coadministration with other medications may increase the risk of cytochrome P-450 3A4 mediated drug interactions. Simvastatin is a substrate for and is primarily dependent on cytochrome P-450 3A4 for elimination, with 78% to 87% of absorbed simvastatin undergoing hepatic metabolism. Although the mechanism is not well understood, cases of rhabdomyolysis have occurred in the setting of increased plasma concentrations of the statin. Inhibition of cytochrome P-450 3A4 by azole containing antifungals has been documented, and may lead to a marked increase in plasma levels of statins. 2–4 Gilad and Laml reported rhabdomyolysis in 2 patients receiving simvastatin who were treated with ketoconazole for fungal dermatitis. 5 The widespread use of statins in the elderly renders patients with prostate cancer at particular risk for this drug interaction. To our knowledge this case represents the first in which prostate cancer managed by a statin was associated with development of rhabdomyolysis when high dose ketoconazole was added to the treatment regimen. The widespread use of statins and the increasing use of ketoconazole in prostate cancer require a higher level of awareness among physicians. It is particularly critical that the urologist and oncologist exercise caution when commencing high dose ketoconazole therapy in patients with androgen independent prostate cancer who are concomitantly receiving 3-hydroxy3-methylglutaryl coenzyme A reductase inhibitors.