As a biology and chemistry major with ongoing interest – fluorinated medications have been an interest of mine for some time. If you have taken organic chemistry – you know that fluorination significantly alters the properties of molecules due to the electronegativity of the fluorine atom. If you are interested in the chemistry of compounds in nature – you may know none of them are fluorinated. I pointed that out in a previous post about fluorinated molecules that are used as medications.
You can imagine my surprise when I received a solution of 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorotetradecane
in the mail yesterday. That’s right C13H17F13. It’s not that people are mailing me random
fluorinated compounds – this is a prescription from a dry eye specialist on the
latest in dry eye care. It all started as a conversation at our last
appointment. He knows I am a nerd and I
stared talking about the lack of available treatments and how it made no sense
to me from a chemical perspective:
Me: “It seems like a
straightforward problem to me, Current chemical
analysis should be able to very accurately characterize the tear film including
the lipid layer and just mix it up as eye drops.”
OD: “I hear you George – and we are getting close to that –
in fact a new drug has just been released that is supposed to keep the tear
layer from breaking up. Are you
interested in trying it?”
Of course, I was.
Dry eye disease in my case is multiple diagnoses and there seem to be no
good solutions for any of them. I end up using non-preservative artificial tears
6 - 8 times per day and even then, get burning and foreign body sensations in the
eye. Worst case - my eyes start burning to the point that I can't focus and have to stop what I am doing. Finding out that the new medication
was a poly fluorinated alkane was a surprise. For the past two weeks I have been
negotiating with the only pharmacy in the country that dispenses this product
along with the pharmacy benefit manager. At one point a retail price of $950/3
ml was quoted and I am in the Medicare doughnut hole. For some unknown reason
and appeal of the denial was granted and I got the prescription mailed to
me. I started it yesterday.
The accompanying package insert is only 2 pages in length.
That is brief relative to most medications.
The results of two clinical trials are described (total of 1,217
patients). The studies were described as multicenter, randomized controlled
clinical trails with a saline placebo. The trials were 57 days in duration. Toxicology
has all been preclinical and mostly bioassays (Ames assay and in vitro
chromosome aberration assay using human peripheral lymphocytes and in vivo
bone micronucleus assays in rats). Long term toxicity studies have not been
done.
I looked at what is known about the lipid layer that is provided
by Meibomian glands in the eyelid. The
resulting secretion mebum is a complex mixture of lipids, waxes, and
other organic molecules that provide a layer over the tear layer so that it
does not evaporate and dissipate as quickly.
For all those details see the open access reference below. One of the advantages of polyfluorination is
that it greatly augments the lipid solubility of organic molecules. That is good if you happen to want a
controllable lipid layer over and aqueous layer, but it may cut both ways.
There is plenty of lipid content in the human body where these compounds can enter.
per- and poly-fluoroalkyl substances (PFAS) are examples of industrial chemicals
that have become environmental contaminants in drinking water, food, and
air. A 2015 study looking at 2011 data
suggested that 97%
of American had PFAS in their blood, although there is some suggestion that
these numbers have been decreased with less production and removals from
products. Technically the dry eye
medication that I have reviewed here is a polyfluorinated alkyl product. I will be following this release closely especially
any after market adverse events and the literature on whether there is concern
that this molecule might accumulate in lipid tissue in the body. Ideally a product will be available that will
mimic Meibomian gland secretion in terms of the lipids that are naturally
there.
The potential dual nature of this medication highlights a
dilemma that many people face every day.
Do you try a medication with potential downsides when the information
about those downsides will take a while to accumulate? To me that is always an informed consent
discussion and it depends a lot on expectations and risk/benefit
considerations. In this case, dry eyes
is a tremendous problem and there seem to be no other reasonable solutions. My
answer currently is a qualified yes.
That may change as more is known about alternative medications that
resemble the natural secretions or the toxicology of the current medication. I
would characterize the level of severity of the problem as moderate. There
are more toxic medications out there and more severe conditions.
George Dawson, MD, DFAPA
References:
1: Chen J, Panthi S.
Lipidomic analysis of meibomian gland secretions from the tree shrew:
Identification of candidate tear lipids critical for reducing evaporation. Chem
Phys Lipids. 2019 May;220:36-48. doi: 10.1016/j.chemphyslip.2019.01.003. Epub
2019 Jan 17. PMID: 30660743; PMCID: PMC6600086.
2: FDA page on PFAS: https://www.fda.gov/food/environmental-contaminants-food/and-polyfluoroalkyl-substances-pfas
3: FDA page on further PFAS study: https://www.fda.gov/news-events/press-announcements/statement-fdas-scientific-work-understand-and-polyfluoroalkyl-substances-pfas-food-and-findings
4: CDC page on Per- and Polyfluoroalkanes and Health: https://www.atsdr.cdc.gov/pfas/resources/pfas-faqs.html
