Background and Metabolism of Statin Drugs
Hyperlipidemia is a common disorder in HIV-infected patients and can result from, or be exacerbated by, the use of antiretroviral therapy.[,,] 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. These agents are the mainstay of treatment for HIV-infected patients with hyperlipidemia. 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 limited or no metabolism via the cytochrome P450 system (Figure 1). 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. Rosuvastatin (Crestor) undergoes minimal metabolism via cytochrome P450 (CYP2C9 and CYP219) and is primarily excreted in a non-metabolized form in the feces. Pitavastatin (Livalo) undergoes metabolism predominantly through glucuronidation (UGT1A3 and UGT2B7), with some minor metabolism via CYP2C9 andCYP2C8. Pravastatin (Pravachol) requires glucuronidation for metabolism, has minimal interaction with the cytochrome P450 system, and is excreted in an unchanged form. Drugs that inhibit the cytochrome CYP3A4 isozymes may increase the plasma level of statins that are metabolized via the CYP3A4 pathway. Because all of the protease inhibitors (PIs) inhibit the CYP3A4 isoenzymes, they have the potential to significantly increase statin levels. No clinically significant interactions occur between statin drugs and nucleoside reverse transcriptase inhibitors (NRTIs) or CCR5 antagonists.
Interaction of Non-Nucleoside Reverse Transcriptase Inhibitors and Statins
Nevirapine (Viramune) and efavirenz (Sustiva) have the potential to induce CYP3A4, which may reduce the plasma levels of statin drugs 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. A separate study found that patients on an efavirenz-based antiretroviral regimen who received simvastatin (20 mg once daily) had less than optimal decreases in their low density lipoprotein (LDL) levels and no major adverse effects. 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 levels of statins which may lead to a reduced lipid-lowering response. Rilpivirine (Edurant) at a dose of 25 mg daily is not likely to cause significant alterations in statin plasma levels. The HHS Antiretroviral Therapy Guidelines include recommendations 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 levels of the statin drugs, which are substrates for CYP3A4 metabolism. The degree of PI inhibition of CYP3A4 varies, with the greatest effect caused by ritonavir (Norvir)-boosted PI combinations. 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). 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. 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. 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. The HHS Antiretroviral Therapy Guidelines include recommendations regarding concomitant use of statin drugs with PI antiretroviral medications (Figure 4).
Interaction of Integrase Strand Transfer Inhibitors and Statin Drugs
The use of integrase inhibitors without additional pharmacokinetic boosting agents (cobicistat, ritonavir) is unlikely to impact plasma levels of statins. The impact of statin plasma levels with use of INSTIs in combination with PIs or boosting agents should be evaluated based on the co-administered drug. The HHS Antiretroviral Therapy Guidelines include recommendations regarding concomitant use of statin drugs with integrase inhibitor antiretroviral medications (Figure 5).
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.[,] 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.[,,,] Delavirdine has been implicated in a case report of severe rhabdomyolysis and acute tubular necrosis when co-administered with atorvastatin (20 mg once daily).