LETTER TO THE EDITOR
Reply
Philip Hansten, PharmD*
* School of Pharmacy, University of Washington, Seattle, Washington 98195-7630, USA
hansten{at}u.washington.edu
I agree with Dr. Williams that simvastatin and lovastatin are more prone than pravastatin to interact with drugs that inhibit cytochrome P450 isozymes. But some of his other points do not survive a careful reading of the scientific data.
First, Dr. Williams states that the interaction between pravastatin and cyclosporine is "widely recognized" to involve P-glycoprotein (PGP) and cites two references (1,2), but neither study provides any scientific support for his claim. Indeed, the limited available information suggests that pravastatin is a substrate for other transporters such as canalicular multispecific organic anion transporter (cMOAT) or organic anion-transporting polypeptide (OATP) (3,4).
More importantly, even after years of frequent use of pravastatin with cyclosporine, there is little evidence that the combination is harmful (5–7), unlike lovastatin and simvastatin, where up to 20-fold increases in statin serum concentrations have been reported and rhabdomyolysis has occurred (1,8–11). Moreover, even if all statins were equally likely to interact with cyclosporine, transplant patients receive other drugs as well, and the possibility of the patient receiving other CYP3A4 inhibitors with lovastatin or simvastatin creates additional concerns (10,11).
Dr. Williams further contends that myopathy following statin-gemfibrozil combinations results from a pharmacodynamic interaction. This was commonly held, but we now know that gemfibrozil substantially increases serum concentrations of lovastatin and simvastatin (12,13). Thus, the interaction is pharmacokinetic; whether a simultaneous pharmacodynamic interaction exists is speculative. Moreover, neither of the references Dr. Williams cited to support myopathy following pravastatin-gemfibrozil contained any actual cases of myopathy.
Dr. Williams cites large outcome trials, but such studies are notoriously misleading in assessing drug interactions. For example, the RALES trial found spironolactone plus angiotensin-converting enzyme inhibitors safe and effective in treating severe heart failure (14). Yet it is clear that in certain predisposed patients—particularly those who get larger doses of spironolactone in the presence of renal disease and diabetes—fatal hyperkalemia can result (15–17). Thus it is with lovastatin and simvastatin where life-threatening rhabdomyolysis has occasionally occurred owing to drug interactions. The fact that serious or fatal drug interactions are rare does not absolve us from preventing them when the scientific evidence allows us to do so.
Finally, one can put statin drug interactions in the context of what we have learned about drug interactions over the past 40 years. The poverty of proposing "class effects" for drug interactions has been repeatedly confirmed, and it is extraordinarily rare for all members of a drug class to interact homogeneously. Nonetheless, it is convenient to say that we have insufficient information to be certain that individual members of a drug class interact differently from each other. If we held all drug interactions to that standard, we could rarely choose one member of a drug class over another in order to reduce the risk of adverse interactions. But for many drug classes, including the statins, we do have sufficient information to choose members of the class that will reduce the drug interaction risk in specific patients. To blur these differences is to put patients at greater risk of a preventable adverse outcome.
 |
References
|
|---|
1. Olbricht C, Wanner C, Eisenhauer T, et al. Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses. Clin Pharmacol Ther. 1997;62:311–321[CrossRef][Medline]
2. Christians U, Jacobsen W, Floren LC. Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors in transplant patients: are the statins mechanistically similar? Pharmacol Ther. 1998;80:1–34[CrossRef][Medline]
3. Yamazaki M, Akiyama S, Ni’inuma K, Nishigaki R, Sugiyama Y. Biliary excretion of pravastatin in rats: contribution of the excretion pathway mediated by canalicular multispecific organic anion transporter. Drug Metab Dispos. 1997;25:1123–1129[Abstract/Free Full Text]
4. Sasaki M, Suzuki H, Ito K, Abe T, Sugiyama Y. Transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II cell monolayer expressing both human organic anion-transporting polypeptide (OATP2/SLC21A6) and multidrug resistance-associated protein 2 (MRP2/ABCC2). J Biol Chem. 2002;277:6497–6503[Abstract/Free Full Text]
5. Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med. 1995;333:621–627[Abstract/Free Full Text]
6. Katznelson S, Wilkinson AH, Kobashigawa JA, et al. The effect of pravastatin on acute rejection after kidney transplantation—a pilot study. Transplantation. 1996;61:1469–1474[CrossRef][Medline]
7. Christians U. Combination of pravastatin and cyclosporine in transplant patients. Clin Pharmacokinet. 1997;32:173–174[Medline]
8. Weise WJ, Possidente CJ. Fatal rhabdomyolysis associated with simvastatin in a renal transplant patient. Am J Med. 2000;108:351–352[CrossRef][Medline]
9. Kusus M, Stapleton DD, Lertora JJL, Simon EE, Dreisbach AW. Rhabdomyolysis and acute renal failure in a cardiac transplant recipient due to multiple drug interactions. Am J Med Sci. 2000;320:394–397[CrossRef][Medline]
10. Vlahakos DV, Manginas A, Chilidou D, Zamanika C, Alivizatos PA. Itraconazole-induced rhabdomyolysis and acute renal failure in a heart transplant recipient treated with simvastatin and cyclosporine. Transplantation. 2002;73:1962–1964[Medline]
11. Maxa JL, Melton LB, Oju CC, Sills MN, Limanni A. Rhabdomyolysis after concomitant use of cyclosporine, simvastatin, gemfibrozil, and itraconazole. Ann Pharmacother. 2002;36:820–823[Abstract]
12. Backman JT, Kyrklund C, Kivisto KT, Wang J-S, Neuvonen PJ. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther. 2000;68:122–129[CrossRef][Medline]
13. Kyrklund C, Backman JT, Kivisto KT, Neuvonen M, Laitila J, Neuvonen PJ. Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not be benzafibrate. Clin Pharmacol Ther 2001;69:340–5
14. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709–717[Abstract/Free Full Text]
15. Schepkens H, Vanholder R, Billiouw J-M, Lameire N. Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: an analysys of 25 cases. Am J Med. 2001;110:438–441[CrossRef][Medline]
16. Berry C, McMurray J. Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone. (letter)Am J Med. 2001;111:587[Medline]
17. Blaustein DA, Babu K, Reddy A, Schwenk MH, Avram MM. Estimation of glomerular filtration rate to prevent life-threatening hyperkalemia due to combined therapy with spironolactone and angiotensin-converting enzyme inhibition or angiotensin receptor blockade. Am J Cardiol. 2002;90:662–663[CrossRef][Medline]
|
Top
References