Drug companies make simpler dosing a priority

Once-a-day regimes already may be in the pipeline

Clinicians are asking for it, patients are crying for it, and pharmaceutical companies are racing to deliver it: simpler dosing for HIV medications.

The growth in drug-resistant HIV in recent years indicates that patients are having difficulty maintaining their drug regimens, and many experts attribute this to the complicated dosing requirements of many antiretroviral medications.

"The antiretroviral failures are, in general, problems with medications where people have difficulty adhering to their medications," says Daniel Kuritzkes, MD, an associate professor of medicine and microbiology in the division of infectious disease at the University of Colorado Health Sciences Center in Denver.

Clinical trials are showing stunning success rates in giving patients some of the newer one- and two-dose daily drug regimens, Kuritzkes adds. Last fall’s 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held in San Francisco, featured positive results from one-daily dosing of these drug regimens:

• the protease inhibitor indinavir (Crixivan) plus ritonavir (Norvir);

• the protease inhibitor saquinavir (Fortovase) plus ritonavir;

• nevirapine (Viramune) plus didanosine (Videx) plus stavudine (Zerit).

ICAAC also had a presentation on a twice-daily ABT-378 and ritonavir combination that had excellent anti-HIV effects in drug-naive and drug-experienced HIV patients. (See story about ABT-378 in AIDS Alert, December 1999, p. 136.)

Simple therapies are most successful

"If we’re going to have to treat people for decades, we’re going to have to make things pretty simple," says Joseph Eron, MD, co-director of the AIDS Clinical Research at the University of North Carolina at Chapel Hill. Eron is involved with ABT-378 research.

"Look at the high blood pressure literature and stuff like that," Eron adds. "It’s really the simple therapies that are the most successful."

Some AIDS advocacy groups are touting the benefits of drug therapies that rely on simpler dosing. For example, the National Association of People with AIDS in Washington, DC, issued a press release touting the benefits of simpler dosing after the U.S. Food and Drug Admini stra tion (FDA) approved in September 1999 stavudine (Zerit) and didanosine (Videx) for use as a first-line combination therapy. The organization asked the FDA to rapidly review a labeling change that would allow Bristol-Myers Squibb Pharmaceutical Research in Wallingford, CT, to offer the combination in a simpler dosing format.

Bristol-Myers had found in clinical trials that the combination was just as effective in once-daily dosing as it was in twice-daily dosing. The studies also indicated patients were able to tolerate the once-daily dosing better.

"The data are clear that people adhere to drugs that are tolerable and that are easy to take," says Craig Nelson, associate director for health education at the National Association of People with AIDS.

"So when you have a drug that has efficacy at lower doses, then it’s good news for patients because we don’t have to take as many drugs, and we can minimize the side effects in our bodies," he adds.

The major toxicity of didanosine is pancreatitis, which has been fatal. Other adverse effects are retinal changes and optic neuritis. The combination of didanosine and stavudine has been associated with increased risk for peripheral neuropathy and liver function abnormalities.

One pill daily may be on horizon

Will there ever be a single HIV pill that patients could take once a day?

It’s possible, and drug companies already are working toward that goal, Eron says. "There was talk at ICAAC about people trying to develop regimens that are entirely once a day."

For instance, Glaxo Wellcome Inc. of Research Triangle Park, NC, has made simpler antiretroviral dosing a priority, says Stephen LaFon, MS, international product development leader for Ziagen.

"While HIV therapy has become, in a lot of people’s perspective, very successful, and we now have tools to suppress the virus down to levels of being undetectable, and we can prolong lives for a long period of time, the medications come with fairly complex treatment regimens," LaFon says.

It isn’t uncommon for patients to take 30 or more pills a day, including prophylaxis drugs. "Pill burdening is a real challenge, and these can be large pills," LaFon adds. "And often these pills can’t be taken with food or must be taken with food, or they can’t be taken with other meds because of drug interactions, and so people end up living their lives around their medication schedule."

But if a patient misses some of his or her doses, it can create long-term problems because of drug resistance.

That’s where a simpler, twice-daily drug like abacavir (Ziagen) can help improve patient compliance, LaFon says.

Meanwhile, simpler combinations

But because antiretroviral therapy requires several drugs to keep the virus in check, pharmaceutical companies also are trying to develop drug combination pills that make things even simpler for patients.

Two years ago, Glaxo Wellcome introduced Combivir, which is a combination of lamivudine (Epivir) and AZT (Retrovir). The company’s research showed better patient compliance with Combivir than with the tablets given individually.

"So instead of taking two pills twice a day, it’s one pill twice a day," LaFon says. "And we’re in the process of carrying that one step further by combining Ziagen and Combivir into one pill."

This way, patients can take a triple-drug therapy in the form of one pill twice a day. The pill will be called Trizivir, LaFon says. "This basically is revolutionary; it’s a switch from 20 or more caplets a day to two."

Before Trizivir becomes available, it must be approved by regulatory agencies, a process that has begun, he adds.

One drawback to dual and triple combination pills is that if patients have an adverse reaction to one of the medications, they must stop taking the entire pill and switch to another therapy regimen. With abacavir, this could be a problem because the drug has adverse effects including headache, nausea, vomiting, malaise, diarrhea, lactic acidosis, and severe hepatomegaly with steatosis, including fatal cases.

But this merely means a patient would have to return to the more complex dosing requirements of a triple therapy featuring individual pills.

"That’s a physician judgment issue," LaFon says. "Some physicians may choose to start with the individual units first and then switch to Trizivir."

Lastly, Glaxo Wellcome is moving toward evaluating its products as once-a-day pills. Lamivudine and abacavir, for example, could become once-per-day pills.

Already, efavirenz (Sustiva) is a one-dose-per-day pill, and as the ICAAC conference demonstrated, other one-per-day pills are being studied.

"The best of all worlds would be to evolve to a once-a-day treatment regimen," LaFon says. "There’s a lot of interest among clinicians to find a suitable once-a-day regimen that is as good as a twice or three-times-a-day regimens."