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Case 5: Discussion

Background and Metabolism of Statin Drugs

The use of highly active antiretroviral therapy (HAART), especially with regimens that include protease inhibitors (PIs), predispose patients to a number of metabolic complications, including hyperlipidemia and lipodystrophy[1,2,3]. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly referred to as statins, work by decreasing synthesis of cholesterol in the liver, and these agents play a critical role in treating hyperlipidemia associated with the use of HAART. As shown in Figure 1, most of the statins undergo significant metabolism via one or more of the cytochrome P450 isozymes located in the gastrointestinal tract and liver, but some have minor or no metabolism via the cytochrome P450 system[4]. Lovastatin (Mevacor), simvastatin (Zocor), and to a lesser extent, atorvastatin (Lipitor) undergo significant metabolism via the cytochrome P450 3A4 (CYP3A4) isozymes. Fluvastatin (Lescol) is metabolized predominantly by CYP2C9 isozymes[5]. Rosuvastatin (Crestor) undergoes minimal metabolism via cytochrome P450 (CYP2C9 and CYP219) and is primarily excreted in a non-metabolized form in the feces[6]. Pitavastatin (Livalo) undergoes metabolism predominantly through glucuronidation (UGT1A3 and UGT2B7), with some minor metabolism via CYP2C9 and CYP2C8[7]. Pravastatin (Pravachol) depends on glucuronidation for metabolism, has minimal interaction with the cytochrome P450 system, and is excreted in an unchanged form[8]. The United States FDA required removal of cerivastatin (Baycol) from the market in 2001 because of the high incidence of rhabdomyolysis[4]. Any drug that inhibits the cytochrome CYP3A4 isozymes can increase the level of statins that are metabolized via the CYP3A4 pathway. All of the PIs and the non-nucleoside reverse transcriptase inhibitor (NNRTI) delavirdine (Rescriptor) inhibit the CYP3A4 isoenzymes and thus have the potential to significantly increase statin levels. No significant interactions occur between statin drugs and nucleoside (or nucleotide) reverse transcriptase inhibitors, integrase strand transfer inhibitors, or CCR5 antagonists. Interactions between antiretroviral agents and lipid-lowering agents in the fibrate class are unlikely to be clinically significant. In addition, antiretroviral medications do not interact with ezetimibe (Zetia), a lipid-lowering agent that works by decreasing absorption of dietary cholesterol in the small intestine.

Interaction of Non-Nucleoside Reverse Transcriptase Inhibitors and Statins

Nevirapine (Viramune) and efavirenz (Sustiva) have the potential to induce CYP3A4 and thus reduce the level of statin drugs that are metabolized via CYP3A4. Although efavirenz is a mixed inhibitor and inducer of CYP3A4, it primarily induces metabolism of CYP3A4 substrates. Co-administration of efavirenz (600 mg) with either simvastatin (40 mg once daily), atorvastatin (10 mg once daily), or pravastatin (40 mg once daily) resulted in significant reductions in the AUC at 0 to 24 hours for all three statins: 58% reduction for simvastatin, 43% for atorvastatin AUC, and 40% for pravastatin[9]. A separate study found that patients on an efavirenz-based antiretroviral regimen who received simvastatin (20 mg once daily) had good but not optimal decreases in their low density lipoprotein (LDL) levels and no major adverse effects[23]. Etravirine (Intelence) is an inducer of CYP3A, but an inhibitor of CYP2C9, CYP2C19, and P-glycoprotein. Efavirenz, nevirapine and etravirine have the potential to decrease plasma concentrations of statins and thus lead to a reduced lipid-lowering response. Rilpivirine (Edurant) is not likel to cause significant alternations in the levels of statins. Delavirdine inhibits CYP3A4, but this antiretroviral medication is rarely used used[10]. The Department of Health and Human Services (DHHS) Antiretroviral Therapy Guidelines include recommendations[11] regarding concomitant use of statin drugs with NNRTI antiretroviral medications (Figure 2).

Interaction of Protease Inhibitors and Statin Drugs

All PIs are metabolized by the cytochrome isozyme CYP3A4 and all inhibit CYP3A4 to some degree. Accordingly, all PIs can increase the plasma concentration of the statin drugs that also undergo metabolism via CYP3A4. The degree of PI inhibition of CYP3A4 varies, with the greatest effect caused by ritonavir (Norvir)-boosted PI combinations[10]. Investigators have performed pharmacokinetic studies in healthy subjects to evaluate the drug interactions between statins and PIs. In one of these studies, a 40 mg dose of either simvastatin, atorvastatin, or pravastatin was administered with the dual PI regimen of saquinavir soft gel capsue (Fortovase) 400 mg twice daily and ritonavir 400 mg twice daily (Figure 3)[12]. The PI combination had a dramatic impact on simvastatin, with the area under the curve (AUC) of simvastatin acid, the active form of simvastatin, increasing by 3000%. The AUC of total active atorvastatin (which is the sum of atorvastatin plus two active metabolites) increased by 79%. Surprisingly, the AUC of pravastatin decreased by 50% in the presence of saquinavir plus ritonavir. No serious adverse events occurred during the study. In separate study, nelfinavir (Viracept) given concomitantly with pravastatin caused a 47% decrease in AUC of pravastatin[13]. Nelfinavir 1250 mg twice daily taken with either atorvastatin (10 mg once daily) or simvastatin (20 mg once daily) caused a 74% increase in the AUC of atorvastatin and a 505% increase in the AUC of simvastatin[14]. Co-administration of lopinavir-ritonavir (Kaletra) with atorvastatin (20 mg once daily) caused a 5.8 fold increase in atorvastatin AUC, whereas lopinavir-ritonavir given with pravastatin (20 mg once daily) had relatively little effect on pravastatin[15]. The DHHS Antiretroviral Therapy Guidelines[11] include recommendations regarding concomitant use of statin drugs with NNRTI antiretroviral medications (Figure 4).

Potential Manifestations Associated with Statin Toxicity

The most significant adverse effects associated with statin use have consisted of skeletal muscle injury and hepatic dysfunction. The manifestations of skeletal muscle injury may include myalgias (2 to 11%), acute myositis (0.5%), and rhabdomyolysis (less than 0.1%). Although the risk of developing myopathy in patients taking statins is very low, it increases substantially with concurrent use of drugs known to inhibit CYP3A4 isozymes[16,17]. Rare reports exist of life-threatening rhabdomyolysis resulting from drug-drug interactions with CYP3A4 inhibitors and statins. The laboratory manifestations of myopathy consist of elevations in one or all of the following: creatine kinase (CK), lactate dehydrogenase, and transaminases. Severe cases of drug-induced rhabdomyolysis may lead to acute renal failure and severe electrolyte imbalances. Several case reports have described these toxicities in patients receiving statins with protease inhibitors and statins[18,19,20,21]. Delavirdine has been implicated in a case report of severe rhabdomyolysis and acute tubular necrosis when co-administered with atorvastatin (20 mg once daily)[22].

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    Figure 1. Metabolism and Excretion of Statin Drugs

    Figure 1
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    Figure 2. Recommendations for the Use of Non-Nucleoside Reverse Transcriptase Inhibitors and Statin Drugs
    This figure is adapted from Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. March 27, 2012;1–239.

    Figure 2
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    Figure 3. Effect of Ritonavir plus Saquinavir on Selected Statin Drugs in HIV-Negative Individuals
    In this study, HIV-negative individuals received pravastatin, atorvastatin, or simvastatin (40 mg each) on days 1-4 and then added ritonavir (400 mg bid) plus saquinavir soft gel capsules (400 mg bid) on days 4-18. This figure shows the impact that ritonavir plus saquinavir had on the AUC of the statin drugs.
    Source: Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS. 2002;16:569-77. Reproduced with permission from Lippincott Williams & Wilkins.

    Figure 3
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    Figure 4. Recommendations for the Use of Protease Inhibitors and Statin Drugs
    This figure is adapted from Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. March 27, 2012;1–239.

    Figure 4