Robertsen Ida, Asberg Anders, Granseth Tone, Vethe Nils Tore, Akhlaghi Fatemeh, Ghareeb Mwlod, Molden Espen, Reier-Nilsen Morten, Holdaas Hallvard, Midtvedt Karsten
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.
Transplantation. 2014 Jun 27;97(12):1266-71. doi: 10.1097/01.TP.0000443225.66960.7e.
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.
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.
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 μgh/L before and 78.5±21.9 μgh/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.
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.
血脂异常是肾移植受者（RTRs）过早发生心血管疾病和死亡的危险因素。使用mTOR抑制剂进行药物治疗会加重血脂异常，因此需要使用氟伐他汀、普伐他汀或阿托伐他汀进行降脂治疗。这些药物可能无法充分降低血脂水平，因此可能需要更强效的药物如瑞舒伐他汀。
我们旨在评估瑞舒伐他汀与氟伐他汀相比在接受依维莫司的RTRs中的降脂效果。安全性评估为瑞舒伐他汀/依维莫司组合在RTRs中的药代动力学（PK）相互作用潜力。对12名接受依维莫司和氟伐他汀（80mg/d）的稳定RTRs进行了12小时的依维莫司PK研究。然后患者换用瑞舒伐他汀（20mg/d），1个月后进行依维莫司/瑞舒伐他汀的12/24小时PK随访研究。所有其他药物保持不变。
在已经接受氟伐他汀的RTRs中，换用瑞舒伐他汀后，低密度脂蛋白胆固醇和总胆固醇分别进一步降低30.2±12.2%（P<0.01）和18.2±9.6%（P<0.01）。依维莫司AUC0-12不受同时使用瑞舒伐他汀治疗的影响，分别为80.3±21.3μgh/L和78.5±21.9μgh/L（P=0.61）。瑞舒伐他汀的平均AUC0-24为157±61.7ng*h/mL，约为文献报道的非移植患者的三倍。没有不良事件发生，所有患者均未出现或发生蛋白尿。
在接受依维莫司的稳定RTRs中，瑞舒伐他汀显示出比氟伐他汀更好的降脂效果。依维莫司/瑞舒伐他汀组合似乎与依维莫司/氟伐他汀组合一样安全。
