Interaction between
Cerivastatin
and
Ritonavir
Major
Metabolism
Basic Information
| ID | DDInter341 and DDInter1607 |
| Interaction | Protease inhibitors (PIs), particularly ritonavir, may significantly increase the plasma concentrations of certain HMG-CoA reductase inhibitors. The mechanism is PI inhibition of CYP450 3A4 metabolism. High levels of HMG-CoA reductase inhibitory activity in plasma are associated with an increased risk of musculoskeletal toxicity, including myopathy and rhabdomyolysis, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death. |
| Management | Simvastatin or lovastatin are considered contraindicated in patients treated with tipranavir and/or ritonavir due to the potential for severe interaction. Red yeast rice (which contains lovastatin) should also be avoided in patients treated with PIs. Fluvastatin and pravastatin are probably safer alternatives, since they are not metabolized by CYP450 3A4. All patients treated with HMG-CoA reductase inhibitors should be advised to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed. |
| References | [1] Cheng CH, Miller C, Lowe C, Pearson VE "Rhabdomyolysis due to probable interaction between simvastatin and ritonavir." Am J Health Syst Pharm 59 (2002): 728-30 [2] Hare CB, Vu MP, Grunfeld C, Lampiris HW "Simvastatin-nelfinavir interaction implicated in rhabdomyolysis and death." Clin Infect Dis 35 (2002): E111-2 [3] Mangum EM, Graham KK "Lopinavir-Ritonavir: a new protease inhibitor." Pharmacotherapy 21 (2001): 1352-63 [4] "Product Information. Fortovase (saquinavir)" Roche Laboratories, Nutley, NJ. [5] "Product Information. Agenerase (amprenavir)." Glaxo Wellcome, Research Triangle Pk, NC. [6] Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al. "Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047." AIDS 16 (2002): 569-577 [7] "Product Information. Prezista (darunavir)." Ortho Biotech Inc, Bridgewater, NJ. [8] Schmidt GA, Hoehns JD, Purcell JL, Friedman RL, Elhawi Y "Severe rhabdomyolysis and acute renal failure secondary to concomitant use of simvastatin, amiodarone, and atazanavir." J Am Board Fam Med 20 (2007): 411-6 [9] "Product Information. Reyataz (atazanavir)." Bristol-Myers Squibb, Princeton, NJ. [10] "Product Information. Viracept (nelfinavir)." Agouron Pharma Inc, La Jolla, CA. [11] Malaty LI, Kuper JJ "Drug interactions of HIV protease inhibitors." Drug Safety 20 (1999): 147-69 [12] Piliero PJ "Interaction between ritonavir and statins." Am J Med 112 (2002): 510-1 [13] Dresser GK, Spence JD, Bailey DG "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet 38 (2000): 41-57 [14] "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical, Abbott Park, IL. [15] Barry M, Mulcahy F, Merry C, Gibbons S, Back D "Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection." Clin Pharmacokinet 36 (1999): 289-304 [16] "Product Information. Lexiva (fosamprenavir)." GlaxoSmithKline, Research Triangle Park, NC. [17] "Product Information. Crixivan (indinavir)." Merck & Co, Inc, West Point, PA. [18] Neuvonen PJ, Backman JT, Niemi M "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin." Clin Pharmacokinet 47 (2008): 463-74 [19] Richter WO, Jacob BG, Schwandt P "Interaction between fibre and lovastatin." Lancet 338 (1991): 706 [20] Lilja JJ, Kivisto KT, Neuvonen PJ "Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin." Clin Pharmacol Ther 66 (1999): 118-27 [21] Neuvonen PJ, Backman JT, Niemi M "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin." Clin Pharmacokinet 47 (2008): 463-74 [22] "Product Information. Lipitor (atorvastatin)." Parke-Davis, Morris Plains, NJ. [23] McMillan K "Considerations in the formulary selection of hydroxymethylglutaryl coenzyme a reductase inhibitors." Am J Health Syst Pharm 53 (1996): 2206-14 [24] Boberg M, Angerbauer R, Fey P, Kanhai WK, Karl W, Kern A, Ploschke J, Radtke M "Metabolism of cerivastatin by human liver microsomes in vitro. Characterization of primary metabolic pathways and of cytochrome P45 isozymes involved." Drug Metab Dispos 25 (1997): 321-31 [25] Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10 [26] "Product Information. Agenerase (amprenavir)." Glaxo Wellcome, Research Triangle Pk, NC. [27] Demarles D, Gillotin C, Bonaventure-Paci S, Vincent I, Fosse S, Taburet AM "Single-dose pharmacokinetics of amprenavir coadministered with grapefruit juice." Antimicrob Agents Chemother 46 (2002): 1589-1590 |
| Alternative for Cerivastatin |
C10A
|
| Alternative for Ritonavir |
J05A
|
Potential Metabolism Interactions
Substrate-Substrate Interaction：If more than one drug is metabolized by the same CYP, it is possible that its metabolism is inhibited because of the competition between the drugs. That means, it can be useful to lower the dosage of the drugs in the drug-cocktail because they remain longer in the organism than in monotherapy.
Inhibitor-Inhibitor Interaction：Combining two or more inhibitors of one CYP, should be compensated by lowering the dosage of these drugs because the metabolism is reduced and the drugs remain longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.
Inhibitor-Substrate Interaction：Combining drugs that have inhibitory effect and are substrates of one particular CYP, should be compensated by lowering the dosage. They rest longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.