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Klinisch pharmakologische Erklärungsmodelle der Cerivastatin-assoziierten Rhabdomyolyse

Pharmacological explanations for cerivastatin associated rhabdomyolysis

  • Themenschwerpunkt „Statintherapie“
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Zusammenfassung

Der Hydroxy-methylglutaryl-Coenzym-A-Reduktase-Hemmer Cerivastatin mußte im Jahr 2001, nur 4 Jahre nach Erstzulassung, aufgrund tödlicher Arzneimittelzwischenfälle wieder vom Markt genommen werden. Die hohe Rate und der Schweregrad der von Cerivastatin verursachten Rhabdomyolysen löste Bedenken bezüglich der Sicherheit aller HMG-CoA-Reduktase-Hemmer (Statine) aus. Cerivastatin weist jedoch im Vergleich zu anderen Staunen eine 16-bis 80fach höhere Frequenz von tödlichen Rhabdomyolysezwischen-fällen auf. Hierfür dürfte eine Kombination von mehreren pharmakokinetischen und pharmakodynamischen Eigenschaften von Cerivastatin verantwortlich sein. So verfügt Cerivastatin innerhalb der Substanzklasse über die höchste Bioverfügbarkeit nach oraler Applikation. Interaktionen mit anderen Arzneimitteln wie Gemfibrozil können einen weiteren Anstieg des Plasmaspiegels von Cerivastatin bewirken, und das Risiko für Nebenwirkungen an peripheren Organen erhöhen. Zudem besitzt Cerivastatin mit etwa 1 pM die niedrigste IC50 zur Inhibierung der HMG-CoA-Reduktase unter allen Statinen. Die Kombination aus hohen systemischen Spiegeln und hoher intrinsischer Aktivität führt potentiell zu Apoptose der Skelettmuskulatur und zellulärer Energieverarmung durch Ubichinonmangel. Die mit Cerivastatin assoziierten fatalen Zwischenfälle beruhen daher vermutlich auf spezifischen pharmakologischen Eigenschaften von Cerivastatin, und können nicht allgemein auf andere Vertreter der Substanzklasse übertragen werden. Die Erfahrung mit Cerivastatin unterstreicht die Wichtigkeit weiterführender Studien selbst an bereits seit langer Zeit am Markt befindlichen Substanzen, und die Bedeutung einer gewissenhaften Berichterstattung über unerwünschte Arzneimittelwirkungen durch jeden klinisch tätigen Arzt.

Summary

Because of fatal cases of rhabdomyolysis the HMG-CoA-reductase inhibitor cerivastatin had to be withdrawn from the global market in 2001.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.

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  1. Universitätsklinik für Klinische Pharmakologie, Währinger Gürtel, 18-20, A-1090, Wien

    Markus Zeitlinger & Markus Müller

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Zeitlinger, M., Müller, M. Klinisch pharmakologische Erklärungsmodelle der Cerivastatin-assoziierten Rhabdomyolyse. WMW 153, 250–254 (2003). https://doi.org/10.1046/j.1563-258X.2003.03029.x

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