Case 5: Discussion

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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 [1-3]. 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. All of the statins, except pravastatin (Pravachol), undergo significant metabolism via one or more of the cytochrome P450 isozymes located in the gastrointestinal tract and liver (Figure 1). Three of the statins undergo significant metabolism via the cytochrome P450 3A4 (CYP3A4) isozymes: lovastatin (Mevacor) simvastatin (Zocor), and to a lesser extent atorvastatin (Lipitor). The drugs lovastatin and simvastatin are administered as lactone pro-drugs that require conversion to the active hydroxyacid form and these lactone pro-drugs maintain a particularly high affinity for CYP3A4. Fluvastatin (Lescol) is metabolized predominantly by CYP2C9 isozymes and rosuvastatin (Crestor) undergoes minimal metabolism via CYP2C9 and CYP219 and is primarily excreted unchanged (non-metabolized). Pravastatin depends on glucuronidation for metabolism and has minimal interaction with the cytochrome P450 system; pravastatin is also excreted in an unchanged form. Unlike lovastatin and simvastatin, pravastatin, atorvastatin, rosuvastatin and fluvastatin are all administered directly as the active hydroxyacid [4]. Any drug that inhibits the cytochrome CYP3A4 isozymes can increase the level of statins that are metabolized via the CYP3A4 pathway. Among the antiretroviral medications, all of PIs as well as the non-nucleoside reverse transcriptase inhibitor (NNRTI) delavirdine (Rescriptor) act as inhibitors of the CYP3A4 isoenzymes and thus have the potential to significantly increase statin levels. There are no significant interactions between nucleoside (or nucleotide) reverse transcriptase inhibitors and statin drugs. 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 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) or ritonavir-boosted PI combinations, followed by indinavir (Crixivan), nelfinavir (Viracept), amprenavir (Agenerase), and saquinavir (Fortovase, Invirase) [5]. Although not as well studied, atazanavir (Reyataz) would be expected to have a moderate effect on CYP3A4, probably similar to or slightly greater than indinavir. 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 400 mg twice daily and ritonavir 400 mg twice daily (Figure 2) [6]. 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%. Interestingly, the AUC of pravastatin decreased by 50% in the presence of saquinavir plus ritonavir [6]. No serious adverse events occurred during the study. In separate study, nelfinavir given concomitantly with pravastatin caused a 47% decrease in AUC of pravastatin [7]. Nelfinavir given 1250 mg twice daily 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 [8]. 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 [9].

Interaction of Non-Nucleoside Reverse Transcriptase Inhibitors and Statins

Nevirapine (Viramune) and efavirenz (Sustiva) both 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. In contrast, delavirdine inhibits CYP3A4 [5]. Both efavirenz and nevirapine have the potential to decrease plasma concentrations of statins and thus lead to a reduced lipid-lowering response. Co-administration of efavirenz (600 mg) with either simvastatin (40 mg once daily) or atorvastatin (10 mg once daily) resulted in a 60% reduction in simvastatin acid AUC and a 35% decrease in total active atorvastatin AUC. Despite pravastatin’s low affinity for CYP3A4 metabolism, co-administration with efavirenz resulted in a 40% decrease the AUC of pravastatin [7]. To the best of our knowledge, there are no formal pharmacokinetic assessments evaluating interactions between the statins and nevirapine or delavirdine.

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 (2-11%), 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 [10,11]. Although rare, life-threatening rhabdomyolysis has been identified in the presence of 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 [12-15]. Delavirdine has been implicated in a case report of severe rhabdomyolysis and acute tubular necrosis when co-administered with atorvastatin (20 mg once daily) [16].

Recommendations

Recommendations regarding concomitant use of antiretroviral medications and statin drugs depend on the degree of drug-drug interaction (Figure 3). Based on available data, simvastatin or lovastatin are not recommended in patients taking a PI or delavirdine [5,17]. In a patient who requires statin therapy and is taking antiretroviral therapy that includes a PI or delavirdine, pravastatin or fluvastatin can be safely used. When atorvastatin is used with PIs or delavirdine it should be used cautiously and initiated at a dose of 10 mg once daily, with many experts advising not exceeding 40 mg. Although rosuvastatin does not have a significant interaction with PIs, one study found a two-fold increase in levels of this drug in a diverse range of Asian patients when compared with levels in Caucasians. Accordingly, the rosuvastain labeling has been changed and a recommended starting dose for Asian patients has been reduced to 5 mg PO qd. All patients taking a PI and a statin together should receive counseling regarding the symptoms and signs of myopathy. All statins appear to be safe for use with efavirenz and nevirapine. An increase in pravastatin dosage may be warranted when co-administered with ritonavir, nelfinavir, efavirenz, or nevirapine due to diminished pravastatin concentrations caused by these antiretroviral medications. Patients taking antiretroviral therapy medications should be instructed to report any signs of muscle weakness, pain, body aches, abdominal pain, or jaundice after starting a statin. Some experts have also advised checking hepatic transaminase levels prior to starting the statin and 12 weeks thereafter. Although lipid-lowering agents in the fibrate class do not have major interactions with antiretroviral agents, their use combined with a statin drug can increase the risk of rhabdomyolysis.

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