Rhabdomyolysis from Cytochrome P-450 Interaction of Ketoconazole and Simvastatin in Prostate Cancer

Hepatitis and rhabdomyolysis in a patient with hormone refractory prostate cancer on ketoconazole and concurrent lovastatin therapy

“…However, this case differs from that reported by Itakura et al [1], in that our patient also developed non-cholestatic hepatitis. Alanine aminotransferase elevations of three times the upper limit of normal are not common (<3%) in patients in clinical-trials of lipid lowering drugs, and those that do occur are often transient and dose related [10].…”

“…Based on the previous case report of Itakura et al [1], and the fact that the predominant metabolic enzyme of both lovastatin and simvastatin is CYP 3A4, it appears likely that the rhabdomyolysis experienced by this patient was related to a ketoconozole/lovastatin drug interaction. Simvastatin and lovastatin are closely related chemically, differing only by a single methyl group [2], although the hepatic clearance of lovastatin (approximately 70%) is somewhat lower than that of simvastatin (approximately 87%) [5].…”

“…It is tempting to speculate that the subsequent liver dysfunction, exacerbated by the underlying fatty infiltration, played a role in raising the plasma levels of lovastatin, which led to the observed rhabdomyolysis. Regardless, we wish to echo the admonition of Itakura et al [1], regarding the heed clinicians must take when administering high-does of ketoconazole to patients on concomitant simvastatin and lovastatin therapy, especially if they are diabetic. Indeed, since there are alternatives to statin therapy (e.g., ezetimibe), it may be worthwhile to avoid this drug class altogether if it is felt that a patient with progressive prostate cancer will benefit from ketoconazole treatment.…”

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Itakura et al [1] have recently reported a case of a 73-year old man with hormone refractory prostate cancer who experienced rhabdomyolysis after treatment with the azole drug ketoconazole plus hydrocortisone while concurrently receiving simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Ketoconazole is a potent inhibitor of the enzyme cytochrome P450 [CYP] 3A4; several statins, including simvastatin and lovastatin, interact with this hepatic microsomal enzyme, which is responsible in significant part for statin clearance [2].

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“…Ketoconazole is a potent inhibitor of the enzyme cytochrome P450 [CYP] 3A4; several statins, including simvastatin and lovastatin, interact with this hepatic microsomal enzyme, which is responsible in significant part for statin clearance [2]. Since the number of men treated with the combination of ketoconazole and hydrocortisone for prostate malignancy is increasing, Itakura et al [1] predicted that rhabdomyolysis will become more prevalent. However, it is not clear if the statin/ketoconazole drug interaction leading to rhabdomyolysis in men with prostate cancer is a general property of the statins as a drug class, or is an event relatively restricted to simvastatin [3].…”