Wednesday, June 25, 2008

Horrible Kiddo Day and 4HPR/ABT-751 cont.

Before I get into another section of my article on Fenretinide and ABT-751 I have to make a formal statement.

Lynley's children acted like horrible little spoiled brats yesterday.

I am not sure what happened. I don't think there was anything in the water. They all slept well. They ate all of their meals. And, of course, we have already completely ruled out any possibility of inferior parenting. Regardless, something was foul and the kids were, um, foul-er. I was amazed at their propensity to not only be mean to each other but to be mean to their loving parents as well. This will go down in history as "Horrible Kiddo Day." From beating each other to screaming because they missed a word in junior scrabble, it was one bad behavior after another. I have never seen so many fits in a week, much less a single day. It is days like this that leave me in a quandary. I just don't know what happened to Lynley's twerps.

Okay, now that I got that off of my chest it is time to get back into my article. Yesterday, I gave a brief introduction and began the process of laying the foundation for my discussion on the Fenretinide (4HPR) / ABT-751 combination. The bulk of my discussion has centered around identifying good research. Today I will talk about the history of Fenretinide and its use in neuroblastoma. An understanding of 4HPR, what it does do, and what it doesn't is key.

WHAT DO WE REALLY KNOW ABOUT FENRETINIDE
A review of what we know about these drugs is pretty worthwhile. I often hear parents talk about 4HPR in an effort to evaluate it for their child and I rarely hear them address the issues that are, perhaps, most important to consider when evaluating this drug. By the end of this section you will know little known secrets to Fenretinide.

Fenretinide is a synthetic retinoid (vitamin A derivative.) 4HPR is believed to effect cytotoxity in cancer cells by mechanisms that include generating reactive oxygen species and by altering sphigolipid metabolism.1,2,3 4HPR has been tested in neuroblastoma patients for over 10 years. There have been several clinical studies (phase I, II, and III) in both adults and pediatrics. 4HPR has been reported to be cytotoxic to neuroblastoma, colorectal, prostate, breast, ovarian, small-cell lung cancer and both acute lymphoid and myeloid leukemias. The drug has also been tested in at least 3 different formulations. Over the years we have learned quite a bit regarding 4HPR. In neuroblastoma, we have learned that results are highly variable. We have seen some heavily pretreated relapsed children achieve significant responses and in some cases even long term remissions. Others, however, have appeared not to respond at all. A review of the literature provides some important clues to this disparity.

Interpatient Variability - It appears that drug absorption is highly variable among patients. For example, while two children may receive the same dose, the drug can actually be absorbed into the body very differently. Some children receive enough drug in their tissues to have an effect while others do not. Understanding why there is such a marked difference is the subject of several studies.

The poor bioavailability of the capsule formulation may have limited responses in clinical trials. Even high-dose schedules of the capsule formulation have obtained relatively low micromolar plasma levels with a wide interpatient variation that has complicated interpretation of response data. Thus, developing improved formulations of fenretinide that obtain higher and/or more consistent plasma levels in a more patient friendly dosing formulation could enhance 4-HPR antitumor activity. Patients that receive higher plasma levels appear to respond better.

Drug formulations - One of the problems with 4HPR is getting enough of it into pediatric patients. During early trials with the capsule formulation kids were required to take as many as 10 capsules at a time. Even at this level not all children were receiving the levels necessary to show activity. Many patients were actually showing more side effects from the corn oil in the capsules than from the drug itself. Furthermore, with so many capsules required, compliance became an issue. Many children were unable to take the amount of capsules required. In fact, one of the later studies was terminated without reaching a maximum tolerated dose due to patient noncompliance with the number of capsules that were needed to be consumed.

THE COOKIE DOUGH FORMULATION
For Fenretinide to be effective we had to find a way to get it into children with adequate absorption and at levels know to provide benefit - enter the cookie dough formulation or Lym-X-Sorb. Many think that the reason that 4HPR was tested in the new Lym-X-Sorb formulation was an effort to make the drug taste better or to simply cram more drug into our children in the hopes of achieving more effective levels. While this is partially true, the real reason for the new formulation is the Lym-X-Sorb itself. It helps the 4HPR become more bioavailable. Essentially Lym-x-sorb acts like a glove that carries the 4HPR from the stomach to the bloodstream, making the drug far more bioavailable. In mice they were able to achieve plasma levels that were 3 to 7 times higher than with the capsule formulation with the same amount of drug. It is hoped that it would provide this same effect in children. Although the phase 1 trial is ongoing at it's highest dosing levels yet, early reports indicate that the same trend is appearing in patients. The hope is that by reducing interpatient variability and increasing absorption children will be able to consistently achieve the levels of drug which have been shown in mice to defeat neuroblastoma. At adequate levels of 4HPR Lym-x-sorb in mice survival was prolonged in both chemo sensitive and highly chemo resistant cell lines.

Well, there you have it, an overview of Fenretinide. How did I do? Tomorrow I will give an overview of ABT-751 and then hopefully get into the very promising combination trial.

With hope, purpose, and lots of words.

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