title: More potent lipid-lowering effect by rosuvastatin compared with fluvastatin in everolimus-treated renal transplant recipients.
abstract: BACKGROUND
  Dyslipidemia is a risk factor for premature cardiovascular morbidity and mortality in renal transplant recipients (RTRs). Pharmacotherapy with mTOR inhibitors aggravates dyslipidemia, thus necessitating lipid-lowering therapy with fluvastatin, pravastatin, or atorvastatin. These agents may not sufficiently lower lipid levels, and therefore, a more potent agent like rosuvastatin maybe needed.
  
  
  METHODS
  We have aimed to assess the lipid-lowering effect of rosuvastatin as compared with fluvastatin in RTR receiving everolimus. Safety was assessed as the pharmacokinetic (PK) interaction potential of a rosuvastatin/everolimus combination in RTR. A 12-hour everolimus PK investigation was performed in 12 stable RTR receiving everolimus and fluvastatin (80 mg/d). Patients were then switched to rosuvastatin (20 mg/d), and a follow-up 12/24-hour PK investigation of everolimus/rosuvastatin was performed after 1 month. All other drugs were kept unchanged.
  
  
  RESULTS
  In RTR already receiving fluvastatin, switching to rosuvastatin further decreased LDL cholesterol and total cholesterol by 30.2±12.2% (P<0.01) and 18.2±9.6% (P<0.01), respectively. Everolimus AUC0-12 was not affected by concomitant rosuvastatin treatment, 80.3±21.3 μg*h/L before and 78.5±21.9 μg*h/L after, respectively (P=0.61). Mean rosuvastatin AUC0-24 was 157±61.7 ng*h/mL, approximately threefold higher than reported in the literature for nontransplants. There were no adverse events, and none of the patients had or developed proteinuria.
  
  
  CONCLUSIONS
  Rosuvastatin showed a superior lipid-lowering effect compared to fluvastatin in stable RTR receiving everolimus. The combination of everolimus/rosuvastatin seems to be as safe as the everolimus/fluvastatin combination.
authors: 1 Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway. 2 Department of Transplant Medicine, Oslo University Hospital, Oslo, Norway. 3 Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway. 4 Department of Pharmacology, Oslo University Hospital, Oslo, Norway. 5 Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI. 6 Center of Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway. 7 Department of Nephrology, Drammen Hospital, Drammen, Norway. 8 Address correspondence to: Ida Robertsen, School of Pharmacy, University of Oslo. P. O. Box 1068 Blindern, 0316 Oslo, Norway.
authors: Ida
authors: I
authors: Robertsen
authors: Anders
authors: A
authors: Asberg
authors: Tone
authors: T
authors: Granseth
authors: Nils Tore
authors: NT
authors: Vethe
authors: Fatemeh
authors: F
authors: Akhlaghi
authors: Mwlod
authors: M
authors: Ghareeb
authors: Espen
authors: E
authors: Molden
authors: Morten
authors: M
authors: Reier-Nilsen
authors: Hallvard
authors: H
authors: Holdaas
authors: Karsten
authors: K
authors: Midtvedt
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004347:Drug Interactions; D057915:Drug Substitution; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D000068338:Everolimus; D005229:Fatty Acids, Monounsaturated / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005464:Fluorobenzenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077340:Fluvastatin; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000009:adverse effects; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009664:Norway; D010641:Phenotype; D011446:Prospective Studies; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000068718:Rosuvastatin Calcium; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D005229:Fatty Acids, Monounsaturated; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D007211:Indoles; D008055:Lipids; D011743:Pyrimidines; D013449:Sulfonamides; D000077340:Fluvastatin; D000068718:Rosuvastatin Calcium; D000068338:Everolimus; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D020123:Sirolimus