A statin challenges the drug interaction status quo
by Chael Needle
LifeGuide [Treatment Horizons]
Maintaining appropriate levels of lipids (fats or fat-like substances in the blood)—“good” cholesterol (HDL-C), “bad” cholesterol (LDL-C), and triglycerides—helps protects against stroke, heart attack, and coronary heart disease (CHD). When dyslipidemia occurs—for example, “bad” cholesterol and triglyceride levels might be high—action is needed. Lifestyle changes may be in order. Medication may also be a treatment option.
Aside from factors such as lifestyle choices and genetic predispositions, living with HIV and managing the virus with antiretrovirals may disrupt your lipid levels—and increase your risk for CHD and other heart-related diseases. The virus itself has been associated with increased LDL cholesterol and decreased HDL cholesterol levels. Certain antiretrovirals are less lipid-friendly than others. NNRTIs and NRTIs have been associated with dyslipidemia. And protease inhibitors (PIs), for example, have been associated with increasing total cholesterol levels. Antiretrovirals may also interact negatively with one of the first-line treatment options for managing lipid levels—statins.
Protease inhibitors, for example, have been shown to increase statin levels in the blood significantly (and increased statins can lead to adverse events like rhabdomyolysis, or muscle fiber breakdown, and liver and skeletal muscle toxicity). While PIs use the cytochrome P450 system as a metabolic pathway, they can also inhibit the system and wreak havoc for other substances, like statins, that need it to metabolize. In this context, inhibition of the system means more statins than needed enter the blood. The PI ritonavir, in particular, has been shown to be a strong inhibitor of this system.
A study recently presented at the IAS conference in Rome showed that a statin called pitavastatin, brand name Livalo, had minimal drug-drug interactions with the PI combo lopinavir/ritonavir (Kaletra), one of the preferred combos for first-line therapy. This and other drug interaction studies were conducted in HIV-uninfected, healthy participants. Livalo, an FDA-approved drug, has been shown to decrease levels of LDL and triglycerides in the blood, as well as increase levels of HDL. The FDA recently made a labeling change to remove the drug-drug interaction precaution of Livalo when taken with lopinavir/ritonavir.
“Among our drug-drug interaction portfolio are frequently used classes of drugs and we wanted to make sure we did our due diligence,” says Craig Sponseller, MD, VP of Medical Affairs at Kowa Pharmaceuticals America, Inc., makers of Livalo, about taking a comprehensive approach to pharmacokinetic, or drug interaction, studies. This approach included looking at drugs that are metabolized by the cytochrome P450 system, including some heart failure drugs, anti-fungals, and PIs, in relation to Livalo.
“We are very please with these results that have been officially added to our label. Also contained in our label is a drug-drug interaction study with another protease inhibitor, atazanavir, which also showed that Livalo has no clinically significant interaction with this PI, as well,” notes Dr. Sponseller. “So what we have been able to show is that, with three protease inhibitors, we do not have significant interaction. To have a statin option that has no label restriction or limitation with commonly used PIs and can deliver up to forty-five reduction in bad cholesterol will be important to healthcare providers managing those with HIV and dyslipidemia.”
Dr. Sponseller commented on the urgency of addressing the management of lipid levels and understanding the complex interactions and metabolic routes of the drugs we ingest. “There are several things that I think are important about this. One is that we’ve got an HIV population that continues to increase and continues to get older,” says Dr. Sponseller, noting that effective therapies are going to continue to be needed and PI-based therapies are going to continue to be central because now treatment is prevention for HIV.
He continues: “As we approach 2015, over fifty percent of those infected with HIV will be over the age of fifty. Age greater than fifty is certainly a risk factor for cardiovascular disease [CVD]. When you look at the causes of death within the HIV-infected population, cancer is first and cardiovascular disease is second.” It is important to note that, as dyslipidemia can be a complication of both HIV and antiretroviral therapies, its management needs a thought-out approach because “typically what ends up happening is dyslipidemia is a mixed picture—it’s an increase in bad cholesterol, an increase in triglycerides, and a decrease in the good cholesterol. That mix is a concerning mix because you have a lipid profile that needs intervention amidst a backdrop of multiple medications,” he says.
Upcoming research will continue to look at the PI class. “In our Phase IV program we are also looking at darunavir/ritonavir as a combination PK study with Livalo,” he says. “Darunavir is frequently used; it’s a preferred protease inhibitor in the combination regimens that are being used today. It’s a first-line recommendation, not an alternative recommendation like lopinavir. So when we look at the darunavir/ritonavir combination it’s important that we have that data in our drug-interaction portfolio as well. We hope to have that completed by the end of the summer and be able to review data in September.”
Chael Needle wrote about an HIV antigen and antibody combination assay in the July issue.