"Embarrassingly simple" tag puts IV chemotherapy drugs in pill form

Taking a pill is the easiest, least invasive way to take medicine, but unfortunately, not all drugs work that way. Now, Stanford scientists have found “an embarrassingly simple solution” that could make almost any drug molecule effective in oral pill form, testing it in mice with chemotherapy drugs that are normally administered through IV infusion.

In essence, what the team has developed is a small molecular tag that can be attached to most drug molecules that makes them more effective as oral pills. This means that not only can current pills work the same with smaller or fewer doses, but other drugs that can’t currently be given orally might now be viable in that form.

“This is an embarrassingly simple solution to an old problem,” said Mark Smith, lead author of the study. “With this strategy, we can accelerate a huge variety of new drugs through the clinic.”

The problem with many oral drugs is bioavailability – how much of the dose is available for the body to absorb. Ideally, drugs need to be both water-soluble, to dissolve in the stomach and pass into the bloodstream, and oil-soluble to get into the cells to do their work. Doing both is tricky, so many drugs skip the water problem and focus on oil solubility, requiring IV infusion instead.

But the new tag is cleverly designed to change the solubility of the drug molecule it’s attached to. It starts off water soluble, but as the drug passes through the stomach or intestinal wall, enzymes there snip off the tag. As such, by the time the drug reaches the bloodstream it’s become oil soluble instead, ready to get to work.

The Stanford team demonstrated the technique in mice by giving them pill versions of chemotherapy drugs that usually need to be given intravenously. The first target was a drug called vemurafenib, which is used to treat melanoma and other cancers. Unfortunately, it’s extremely insoluble in water, so patients need to take four large pills twice a day to wring out even a tiny amount of the drug.

But once the researchers added their tag to the molecule, its bioavailability jumped from almost nothing to 100%. That means much smaller doses would be needed, and more patients would respond better to the therapy.

“At the outset of the project, we were merely hoping to make drugs soluble in water,” said Smith. “With this example, we went way beyond our expectations.”

So the scientists took it to the next level. They attached the tag to paclitaxel, an IV-infused chemotherapy drug long used to treat breast, lung, prostate, ovarian, bladder and pancreatic cancers. Then they administered oral pills to mice with pancreatic cancer.

Sure enough, this oral paclitaxel performed well – even better than a standard IV dose. This marks the first report of the drug being effective orally, and the team saw no signs of toxicity.

“This could transform the way millions of patients around the world receive chemotherapy,” said Smith. “They’ll have the convenience of staying home to receive care, and they won’t have to do long infusions or receive steroids.”

Of course, it’s still very early days for the research, with human tests required before any conclusions can be drawn. But the team is hopeful that the tag could make a huge range of drugs more viable in pill form, reducing discomfort and side effects of IV administration.

The research was published in the journal Nature Communications.

Source: Stanford University