[Clinico-pharmacologic explanation models of cerivastatin associated rhabdomyolysis].
Because of fatal cases of rhabdomyolysis the HMG-CoA-reductase inhibitor cerivastatin had to be withdrawn from the global market in 2001. The high frequency and severity of cerivastatin-associated rhabdomyolysis caused concerns about the safety of the entire class of HMG-CoA-reductase inhibitors (statins). Still, the frequency of deadly incidents of rhabdomyolysis with cerivastatin was 16 to 80 times higher than with other statins. This seems to be due to a combination of several pharmacokinetic and pharmacodynamic characteristics of cerivastatin. Cerivastatin shows the highest oral bioavailability within its class. Interactions with other drugs like gemfibrocil may cause further elevation of cerivastatin plasma levels, thereby leading to higher frequencies of side effects in peripheral organs. With approximately 1 pM cerivastatin shows the lowest IC50 for inhibition of HMG-CoA-reductase of all statins. The combination of high systemic drug levels and high intrinsic activity potentially leads to apoptosis and energy-depletion of skeletal-muscle cells. Therefore cerivastatin-associated fatal rhabdomyolysis seems to be based on specific pharmacokinetic and pharmacodynamic properties of cerivastatin, and is not a general characteristic of all members of this drug-class. The experiences with cerivastatin support the importance of clinical studies even about well established drugs, and underline the relevance of precise reporting of adverse events by each physician.
Zeitlinger
Markus
M
Universitätsklinik für Klinische Pharmakologie, Währinger Gürtel 18-20, A-1090 Wien.
Müller
Markus
M
D000818:Animals; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D001682:Biological Availability; D002423:Cause of Death; D004347:Drug Interactions; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D011725:Pyridines / Q000493:pharmacokinetics / Q000633:toxicity*; D012206:Rhabdomyolysis / Q000097:blood / Q000139:chemically induced* / Q000401:mortality; D012307:Risk Factors; D016019:Survival Analysis
D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; C086276:cerivastatin