Two years of gratitude to Katherine Sharpe

i-0668a6d6a86fde9aa84ea356c6a0daa6-2006.07.25 Katherine SeedI had only been blogging for four-and-a-half months when I got an e-mail two years ago today from someone named Katherine Sharpe at Seed Media Group in New York City. Seems they had started this thing a couple months earlier with 14 blogs, many of which I had already read regularly. I figured that Ms. Sharpe just wanted me for some reader focus group but after I read the e-mail again, it appeared that she was inviting me to join ScienceBlogs. We hung out the Sb Terra Sig shingle two months later, 9 June 2006, with a diatribe containing all you ever wanted to know (or didn't) about my life story and secret attraction to media.

I really only started this blog to fulfill my need to be a public educator and health advocate and I never thought that more than 50 people were reading (in reality, no more than 50 people were reading on good days; it's just that one was Katherine). Things have grown somewhat since but the best part of moving the blog here has been the larger audience, community, and the great readers and friends, in research and otherwise, that I have made around the world.

More broadly, Katherine was instrumental in the growth of this larger ScienceBlogs entity and its further expansion, passing the torch to medical journalist Virginia (Ginny) Hughes late last year. So, I guess I also have to thank Ginny for allowing me to stay here.

Katherine remains in a freelance capacity with Seed Media Group and is pursuing other projects. She is a tremendous writer in her own right and is editor of the remarkable 400 Words storytelling print and web series for which she has received recognition from Newsweek and Utne Reader.

So just as the first wave of ScienceBloggers has Christopher Mims to thank (now at SciAm), we in the second wave have deep gratitude and respect for our dear Ms. Sharpe.

Miss Katherine, I'm still not sure what you saw in this little ol' blog in its infancy but I'm grateful for your confidence. Thanks both for your friendship and for this great personal and professional life experience.

Photo credit: Abel Pharmboy, 25 Jul 2006, at the offices of Seed Media Group, NYC - that is also Orac's elbow sticking out of his lucite box.

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Here here! I didn't have as much interaction with Katherine as you, Abel, but she has certainly done much for Sb and the bloggers here.

Dear Abel, the following is completely OT, and I apologize for sticking it in this thread.

Have you seen this NYTimes article - "Drug Makers Near Old Goal: A Legal Shield"? Its primary focus is on a legal issues in drug trials, using the case of Johnson and Johnson's 'Ortho Evra' birth control patch as the principal example. The patch apparently delivered much higher doses of estrogen compared to oral pills, which resulted in higher rates of blood clots, strokes, and deaths. Of course, the company knew of these dosage issues beforehand but chose not to inform the public, etc.
Here's the interesting part, referring to the pharmacokinetics involved -

But a crucial trial completed in 1999 showed that the patch delivered 30 to 38 micrograms of estrogen into the bloodstream each day, according to company documents.
Because up to half of the estrogen in pills is lost in the digestive tract before it reaches the blood, the study suggested that the patch delivered an amount of estrogen that could be as high as a pill containing 76 micrograms of estrogen. In 1988, the F.D.A. banned birth control pills with more than 50 micrograms of estrogen.
But the study's author, Dr. Larry Abrams, who has since retired from Johnson & Johnson, decided to apply a 'correction factor' to the results of the 1999 trial, according to documents. He claimed that the patch actually delivered about 40 percent less estrogen than the trial results showed - about 20 micrograms a day.
Dr. Abrams made the change, according to his deposition, to adjust for the different ways the body metabolizes hormones from pills and patches. This adjustment was never part of the study protocol, a plan filed with the F.D.A..

I am curious about the difference in the pharmacokinetics of a drug delivered as a pill as compared to through a patch. It would be awesome if you could explain the science involved in this case. Are there situations where the 40% fudge factor Abrams/J&J applied could be valid? Why couldn't they simply reduce the size of the patch to reduce dosage?

By Stagyar zil Doggo (not verified) on 06 Apr 2008 #permalink

@Stagyar-Zil-Doggo: No problem, questions are welcome anywhere, anytime.

For a quick discussion of the legal aspects of this NYT article, Scott Hensley has a nice post up today at WSJ Health Blog on the legal argument of pre-emption being used by drug companies to say that since the FDA approved the drug/formulation, they cannot be held liable.

Regarding your question about PK differences between a drug taken orally vs. transdermally, the oral route usually requires higher doses since the drug, when absorbed in the intestines, must get past the phase I and phase II drug metabolizing enzymes of the liver before the blood distributes to the rest of the body. The transdermal route initially bypasses this so-called "first-pass" metabolism and blood containing the drug goes around the systemic circulation before seeing the liver. Hence, a patch with an amount of drug equal to that of an oral dosage form would most often give rise to higher blood concentrations.

However, the 40% fudge factor is 1) really, really variable and 2) depends a great deal on the drug itself. Human pharmacokinetics are far more variable than most folks realize and transdermal drug delivery is notorious for even more variability as it can be influenced by what you had on your skin before applying the patch, local blood flow, temperature, pressure (esp important when the OC patches are put around the waist/hips area).

Long answer to your question - I'd be very interested to know the standard deviations from the mean values cited in this report to know if the differences in blood concentrations were statistically different anyway.

Thanks for responding, Abel.

Not knowing anything at all about the subject, I am guessing that -
a) J&J compared blood levels of Estrogen in both groups of patients.
b) They calibrated the size of the patch to the minimum that would result in a high fraction (99%? 99.9%?) of users achieving the predetermined minimum level required for efficacy.
c) For this size of the patch, they found their blood Estrogen level distribution to have a fat tail at the high end, specifically at levels high enough to cause thrombi/strokes/death. Presumably, oral tablets calibrated according to b) above result in a far smaller fraction of users with dangerously high levels. I'm guessing this is because in general most of the drug in a pill is absorbed into the body, but only a small fraction of the drug in a patch is.

So far, so good. But I don't see how one could apply a 40% fudge factor to this. Particularly as you want to cheat and apply it to just the high end of the distribution, not to all of it, as the latter will show your drug to be ineffective for many people.

By Stagyar zil Doggo (not verified) on 07 Apr 2008 #permalink