Expanded Portfolio

A new study reports on the drug-drug interaction between pitavastatin and a common PI combo
by Chael Needle

Last year, A&U reported on a study that demonstrated minimal drug-drug interactions between Kowa Pharmaceuticals’ Livalo, or pitavastatin, and the anti-HIV protease inhibitor (PI) combination lopinavir/ritonavir. A pharmacokinetic study presented at last month’s International AIDS Conference shows similar results for Livalo and darunavir/ritonavir.

Statins are the recommended first-line therapy for those living with HIV-1 infection to manage dyslipidemia, a condition where appropriate levels of lipids—“good” cholesterol (HDL-C), “bad” cholesterol (LDL-C) and triglycerides—are out of balance. The condition can lead to stroke, heart attack, and coronary heart disease (CHD).   

Patients living with HIV and on antiretrovirals need to be careful about which statin they take. “Dyslipidemia among patients with HIV-1 infection are due to, not only the viral disease itself, but antiretroviral therapy as well, particularly HIV protease inhibitors. For this reason, identifying appropriate dyslipidemia treatments, like statins, are a critical part of therapy for people living with HIV-1 infection,” shares Craig Sponseller, MD, Vice President of Medical Affairs at Kowa.

Darunavir, for example, is not easily paired with many statins because of negative drug-drug interactions. This is not the case for Livalo, according to the study. When darunavir/ritonavir and Livalo are co-administered, there was no effect on Livalo or the PI agents in healthy volunteers, notes Dr. Sponseller. “Not only do we want to show that levels of Livalo do not increase to avoid statin toxicity, but also to show that levels of co-administered therapeutic agents do not significantly change or compromise their therapeutic benefit,” he adds.

The primary reason that Livalo confers a therapeutic benefit is its reliance on a particular metabolic pathway in the body. It’s what differentiates Livalo from other statins. Says Dr. Sponseller: “Livalo avoids the main metabolic pathway of approximately seventy-five percent of all drugs metabolized, the cytochrome P450 (CYP) enzyme system. Many essential medicines, including therapies commonly used by HIV/AIDS patients, are strong CYP inhibitors.”

Dr. Sponseller pointed out other highlights of Livalo: “The ability of Livalo to reduce ‘bad cholesterol,’ decrease triglycerides, and improve ‘good cholesterol’ has been well established. In Phase III, non-inferiority studies, Livalo 4mg demonstrated a mean LDL-C reduction up to forty-five percent. Compared to other statins available to patients, the 2mg and 4mg doses of Livalo were comparable to the most commonly prescribed doses of atorvastatin (10mg and 20mg) and simvastatin (20mg and 40mg). In a separate study of elderly patients with primary hyperlipidemia or mixed dyslipidemia, Livalo also demonstrated significantly greater LDL-C reduction compared with pravastatin.” 

Approved for use since 2003 in Japan and subsequently in other regions such as China, Taiwan, and the European Union, and since 2009 here in the U.S., the safety and tolerability of Livalo has been well established.

“For the U.S. approval, ten controlled short-term (eight to twelve weeks) trials and four extension trials (forty-four to sixty weeks) were conducted. These trials enrolled over 4,700 patients, and found that discontinuation rates were less than four percent and there were no reports of myopathy, myositis, or rhabdomyolysis. The study included the general population; patients at higher risk for CHD; patients with type 2 diabetes mellitus and combined dyslipidemia; and elderly patients age sixty-five and older,” he says.

“While the current study was conducted with healthy adult volunteers, we are currently conducting a clinical trial in patients with HIV-1 infection who also have been diagnosed with dyslipidemia. The study period is over twelve weeks that includes a fifty-two-week safety extension. We anticipate this data very soon.” 

Livalo’s dosing restrictions profile is also worth mentioning. Notes Dr. Sponseller: “Based on the FDA’s review of current statin labels and most recent drug-drug interaction studies, the FDA [outlined] new dosing recommendations and limitations for certain statins. After review of the data, including that of Livalo—not only with darunavir/ritonavir, but also with other HIV PIs—no dosing restrictions or limitations were recommended for Livalo when in combination with these PIs.”

As people living with HIV/AIDS are living longer, “the HIV/AIDS patient community will now be faced with new health issues—for example, we know that the risk for coronary heart disease is about ten times greater than the general population,” says Dr. Sponseller. “Since advanced ARVs (of which many are strong CYP inhibitors), along with the disease state, further drive dyslipidemia in these patients, it will be important for physicians to approach lipid-modifying therapy with treatment options where their full dosage range can be utilized as well as help avoid untoward drug interactions and minimize any effect on HIV regimens. It is through finding the right regimen for those living with HIV-1 infection that we can help provide potentially better treatment.”

Chael Needle wrote about the possible risks and benefits of breastfeeding to prevent mother-to-child transmission.

August 2012