Severe rhabdomyolysis due to rosuvastatin in a liver transplant subject with human immunodeficiency virus and immunosuppressive therapy-related dyslipidemia

Abstract

Statins are relatively safe first-line agents to use in the setting of dyslipidemia associated with immunosuppressive therapy in subjects undergoing liver transplantation, and also in HIV-infected patients with dyslipidemia due to antiretroviral drugs, especially ritonavir-boosted protease inhibitors. Rosuvastatin, a new statin, has demonstrated higher potency than previously released statins and is not extensively metabolized by the liver P450 system; therefore, the probability of deleterious pharmacokinetic interactions with commonly used immunosuppressants and antiretroviral drugs is reduced. We present the first case of severe rhabdomyolysis in a liver transplant patient receiving rosuvastatin for the treatment of immunosuppressive therapy-related grade IV dyslipidemia, an HIV-infected subject on protease inhibitor-sparing HAART, that resolved after rosuvastatin withdrawal, probably related to interactions between calcineurin inhibitors and hepatic rosuvastatin uptake transporters such as Organic Anion Transporting Polypeptides (OATPs). Liver Transpl 17:331-333, 2011. V C 2011 AASLD.Received September 22, 2010; accepted November 11, 2010. Dyslipidemia due to immunosuppressants (ISs) is common (45%-69%) after liver transplantation (LT) 1 and is also a frequent side effect of highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV)-infected patients receiving ritonavir-boosted protease inhibitors (r-PIs). 2 In the setting of dyslipidemia after LT, statins are appropriate and well-tolerated first-line agents. 1 Rosuvastatin (ROS) is not extensively metabolized by cytochrome P450 3A4 (CYP3A4) and is more effective than pravastatin for the treatment of both low-density lipoprotein cholesterol and triglyceride levels in HIV1-infected subjects who have dyslipidemia and are receiving r-PIs. 3 The most serious adverse effects of statins are related to muscle injury and increases in liver enzymes in a dose-dependent manner. 4,5 However, the rates of creatine kinase (CK) elevations and myopathy (CK elevations >10 times the upper limit of normal), whether or

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“…1 The lipid values of our subject remained within normal ranges before liver transplantation, and hyperlipidemia was evident 4 months after liver transplantation in During the follow-up, the levels of cholestatic liver enzymes (gamma-glutamyl transpeptidase and alkaline phosphatase) remained elevated and even rose despite the significant improvement in the bilirubin levels after partial splenic embolization. The cholesterol and triglyceride levels did not improve with increased doses of rosuvastatin.…”

Assessing Trans-Inhibition of OATP1B1 and OATP1B3 by Calcineurin and/or PPIase Inhibitors and Global Identification of OATP1B1/3-Associated Proteins

“…Currently, tacrolimus is the primary immunosuppressant used by transplant recipients [ 53 , 54 ]. A case of severe rosuvastatin-related rhabdomyolysis has been reported approximately 1 month after switching to an intensified tacrolimus dosing regimen [ 59 ]. The inhibition of tacrolimus on rosuvastatin uptake in human SCH, including its trans -inhibition and long-lasting inhibition characteristics, is worth further investigation to elucidate the clinically relevant potential of OATP-mediated DDIs via tacrolimus.…”

“…Although tacrolimus does not cause DDIs against atorvastatin [ 20 ] or simvastatin [ 27 ], DDIs of tacrolimus have been reported against the OATP1B1 substrates [ 56 , 57 ] cerivastatin and pravastatin, in which long-term treatment of tacrolimus increased the area under the curve of the plasma concentration time profile (AUC) of cerivastatin by 1.5-fold in renal transplant recipients [ 58 ] and that of pravastatin by ~10-fold in two pediatric and adolescent recipients who received cardiac transplants [ 25 ]. In addition, rhabdomyolysis was noted in a case report of a liver transplant recipient receiving rosuvastatin and tacrolimus [ 59 ]. A prior study reported no preincubation-induced trans -inhibition of tacrolimus against OATP1B1 and OATP1B3 [ 4 ].…”

Implications of integrase inhibitors for HIV-infected transplantation recipients: Raltegravir and dolutegravir (S/GSK 1349572)

“…statins) that can cause rabdomyolysis (13)(14)(15)(16)(17). In addition, one can not entirely exclude the possibility that the concern for rabdomyolysis caused by concomitant use of RAL and statins may be further enhanced by CNIs due to disturbance of statin uptake into the liver by organic anion transporting polypeptides (18). On the other hand, one case of grade 4 CPK elevation was observed during phase II trials of DTG, but it was exercise-related, transient, and asymptomatic (10).…”