ACRIA Update Vol. 10 No. 2 Spring 2001
Tim Horn
Scanning the list of all the drugs currently in development, it's hard not to notice some very familiar names: AZT (Retrovir)® d4T (Zerit)® efavirenz (Sustiva)® nelfinavir (Viracept). While these four drugs are approved and being used by a large number of people, their manufacturers have taken them back to the lab for pharmaceutical facelifts. After all, it takes more than just a strong efficacy record for these drugs to remain popular treatment options. They must also be easy to take. So pharmaceutical companies are scurrying to find new ways to reduce the number of pills-and the number of times these pills need to be taken every day-in order to make these drugs more attractive to those of us who are always "in the market" for the next best thing.
The process by which older drugs are tweaked to make them more attractive is called "reformulation." One of the first drugs to undergo reformulation was saquinavir, Hoffmann-LaRoche's protease inhibitor. Invirase, the first formulation of saquinavir approved, suffered from "poor bioavailability"-only a small percentage of the drug actually found its way into the bloodstream. This drawback considerably weakened saquinavir's activity against HIV and caused the development of drug resistant virus in many people who used it. In response, the manufacturer repackaged the drug into capsules made of soft gelatin (the original capsules were made of hard gelatin) to increase the amount of drug released in the gut. While treatment activists grumbled that reformulation work should have been completed before-not after-the drug was approved, the experience of saquinavir (now sold as Fortovase) proved that it's never too late to make important changes.
Saquinavir is not the only example of approved anti-HIV drugs that have undergone reformulation. In September 1997, Glaxo Wellcome (now GlaxoSmithKline) released Combivir, a single tablet containing both AZT (Retrovir) and 3TC (Epivir). More recently, GlaxoSmithKline received FDA approval for Trizivir, a three-drugs-in-one tablet containing Retrovir, Epivir, and abacavir (Ziagen). These combination tablets successfully reduce the number of pills that need to be taken on a daily basis.
Bristol-Myers Squibb's ddI (Videx) has also gone through its share of reformulations. First the size of the 100 mg chewable tablets was decreased and infused with a more tolerable mandarin orange flavor. This was followed by the development of the 200 mg Videx tablets and FDA approval to use the drug only once a day. Last year, the company received approval for enteric-coated Videx (VidexEC), a capsule that can be taken once a day without the need for chewing or dissolving in water. Although ddI takers must still be mindful of dietary restrictions-it still needs to be taken on an empty stomach-the capsules do away with that chalky orange taste first thing in the morning and can be taken at the same time as other anti-HIV meds.
Last but not least is delavirdine (Rescriptor), a non-nucleoside reverse transcriptase inhibitor marketed by Agouron Pharmaceuticals. Instead of four 100 mg tablets that need to be dissolved in water and taken three times a day, the manufacturer has developed a 200 mg tablet that can be instantly swallowed, also three times a day. A twice-daily dosing schedule for the new 200 mg tablets is currently being studied.
As for reformulations currently under way, the first worthy of mention is Aztec, an "extended release" version of AZT. This drug is being developed at glacial speed-the last time data supporting its use were presented was at the 11th International AIDS Conference in 1998! Still, Verex Laboratories, the manufacturer of the drug, contends that it will be an important option for people wanting to simplify their regimens. Aztec requires one pill to be taken once a day and, if combined with other once-daily drugs (e.g., Videx EC or Sustiva), will allow for a complete one-time daily regimen.
As with VidexEC, Bristol-Myers Squibb has been reformulating d4T (Zerit) for once-daily administration. ZeritEC is in clinical trials using a once-daily 100 mg dose and is being compared to the twice-daily 40 mg dose that is currently being used in clinical practice.
Another reformulation in the making involves nelfinavir (Viracept), Agouron Pharmaceuticals' protease inhibitor. Right now, the typical pill burden is five 250 mg Viracept tablets twice a day-that's a total of ten pills to meet the 1,250 mg daily requirement. The new 625 mg tablets being developed would reduce the pill count to two tablets twice a day.
As for the non-nucleoside reverse transcriptase inhibitors, Boehringer-Ingelheim is conducting studies of once-daily nevirapine (Viramune). If approved-the company will be checking in with the FDA later this year-people taking Viramune will only need to swallow two 200 mg tablets once a day instead of the current dosing schedule of one 200 mg tablet twice a day. Last but not least is efavirenz (Sustiva), a drug that already boasts once-daily usage. To make a good thing even better, DuPont Pharmaceuticals is hoping to combine the current three 200 mg capsules into a single 600 mg capsule.
While it's unlikely that these new formulations will increase the effectiveness of these drugs, it's safe to say that some new and improved formulations will make a world of difference in the way the drugs are viewed and, ultimately, taken on a daily basis. Less is sometimes definitely more. It looks as if we're finally going to get it.
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