Drug–Drug Interactions Between HMG-CoA Reductase Inhibitors (Statins) and Antiviral Protease Inhibitors

Abstract

The HMG-CoA reductase inhibitors are a class of drugs also known as statins. These drugs are effective and widely prescribed for the treatment of hypercholesterolemia and prevention of cardiovascular morbidity and mortality. Seven statins are currently available: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Although these drugs are generally well tolerated, skeletal muscle abnormalities from myalgia to severe lethal rhabdomyolysis can occur. Factors that increase statin concentrations such as drug-drug interactions can increase the risk of these adverse events. Drug-drug interactions are dependent on statins' pharmacokinetic profile: simvastatin, lovastatin and atorvastatin are metabolized through cytochrome P450 (CYP) 3A, while the metabolism of the other statins is independent of this CYP. All statins are substrate of organic anion transporter polypeptide 1B1, an uptake transporter expressed in hepatocyte membrane that may also explain some drug-drug interactions. Many HIV-infected patients have dyslipidemia and comorbidities that may require statin treatment. HIV-protease inhibitors (HIV PIs) are part of recommended antiretroviral treatment in combination with two reverse transcriptase inhibitors. All HIV PIs except nelfinavir are coadministered with a low dose of ritonavir, a potent CYP3A inhibitor to improve their pharmacokinetic properties. Cobicistat is a new potent CYP3A inhibitor that is combined with elvitegravir and will be combined with HIV-PIs in the future. The HCV-PIs boceprevir and telaprevir are both, to different extents, inhibitors of CYP3A. This review summarizes the pharmacokinetic properties of statins and PIs with emphasis on their metabolic pathways explaining clinically important drug-drug interactions. Simvastatin and lovastatin metabolized through CYP3A have the highest potency for drug-drug interaction with potent CYP3A inhibitors such as ritonavir- or cobicistat-boosted HIV-PI or the hepatitis C virus (HCV) PI, telaprevir or boceprevir, and therefore their coadministration is contraindicated. Atorvastatin is also a CYP3A substrate, but less potent drug-drug interactions have been reported with CYP3A inhibitors. Non-CYP3A-dependent statin concentrations are also affected although to a lesser extent when coadministered with HIV or HCV PIs, mainly through interaction with OATP1B1, and treatment should start with the lowest available statin dose. Effectiveness and occurrence of adverse effects should be monitored at regular time intervals.

Mixed–effects analysis of increased rosuvastatin absorption by coadministered telmisartan

“…[17,18] Rosuvastatin is a substrate of hepatic uptake transporters (OATP1B1, OATP1B3, OATP2B1, and NTCP) and efflux transporters such as BCRP, and there are many clinically meaningful DDI data. [15,19,20] Telmisartan is an inhibitor of MRP, BCRP in in vitro, [21] but, as yet, there is no reported case of clinical transporter-mediated DDI of telmisartan as a perpetrator. In our final model, telmisartan affects the absorption process of rosuvastatin rather than its metabolic elimination.…”

Managing drug interactions in HIV-infected adults with comorbid illness

“…As a result, greater increases in serum concentrations of these statins occur when they are coadministered with potent CYP3A4 inhibitors such as protease inhibitors or cobicistat. 46,47 As an example, a 31-fold increase in the area under the curve for simvastatin was seen when this statin was coadministered with ritonavirboosted saquinavir in healthy volunteers. 48 Although drug interaction data are not available for newer protease inhibitors or cobicistat, both lovastatin and simvastatin are contraindicated for patients receiving these agents.…”

Antiviral drug discovery: broad-spectrum drugs from nature

“…Antiviral effects of statins have also been described for HBV, HIV, influenza virus, DENV, HCMV and norovirus [161][162][163][164][165][166][167][168][169] . However the antiviral efficacy of statins in vivo was only marginal and drug-drug interactions with DAAs have been reported 170,171 . While this terminated further use of statins as antiviral drugs, the data taken together underline the important role of the host´s lipid metabolism in viral replication 78 .…”