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The pricing for esketamine is unconscionable. It’s just one stereoisomer of ketamine, which btw works fine. https://www.npr.org/sections/health-shots/2019/03/05/700509903/fda-clears-esketamine-nasal-spray-for-hard-to-treat-depression
This is Martin Shkreli with a very thin cover story. It’s disgusting we let this happen.
I’m still enough of a capitalist to not want to nationalize all drug development but......sorely tried when shit like this happens. Also see: anti-HIV drug cost
Whoops my bad. A note on enantiomers https://en.m.wikipedia.org/wiki/Enantiomer - think left and right hand images of molecules. Sinister vs rectus gives us the s and r designations. s-ketamine -> esketamine. Dexter and laevus give us d,l nomenclature for same thing.
Very generally speaking the synthesis of both enantiomers together is easier and/or cheaper than a pure r- or s-. Often time one is more biologically active with either much higher potency or even complete (in)activity
You can imagine a in/active scenario where twice the amount of the mixture produced the same effect as the active isomer. Most of the stuff that I deal with where these issues arise (the amphetamines), well, it’s complicated.
Metabolism / excretion rates can differ and the “inactive” isomer is typically just “the significantly less potent” isomer.
( can’t remember if I dropped the terms racemate or racemic mixture yet- that means both isomers are present )
Anyway, Adderall. What does it have to do with esketamine? Well Adderall is a “combination drugs containing four salts of the two enantiomers of amphetamine”. d-amp is the more active isomer, l-amp is the less active. The hydrochloride salt would be fairly typical
in good old not at all re-patentable speed. Adderall has some weird witches brew of saccharate, sulfate and aspartate monohydrate salts of the isomers.
Somehow, someway it was shown (I ASSUME) that this bizarre mixture outperformed good old d-amphetamine HCl for ADHD and narcolepsy. And d-methamphetamine HCl too since that was already approved for the same indications.
I have doubts.
Now, it isn't insane that weird witches brew of enantiomers and salts would have different efficacy in vivo as medicine. there may be lesser targets (aka "off target") where the relative potency of isomers is different from primary target and this may matter to therapeutic effect
I think (?) it was alleged the salts gave different kinetics (think time course) of something or other having to with getting into the brain and having effect. but pharma is really good at formulating the pill/capsule/whatever to manipulate the delivery rates.
so I'd want to know exactly what was being compared in the experiments that justified the approval of the patent and the FDA approval.
circling back to esketamine (s-ketamine), I do wonder what on earth justified giving this new patent protection versus good old cheap ketamine formulated for nasal administration in the generics market.
from the wikipedia
"A number of studies have suggested that esketamine has a more medically useful pharmacological action than arketamine or racemic ketamine.[citation needed]" < NSS!!!!!
"A number of studies have suggested that esketamine has a more medically useful pharmacological action than arketamine or racemic ketamine.[citation needed]" < NSS!!!!!
also "However, another study found no difference between racemic and (S)-ketamine on the patient's level of vigilance.[21] Interpretation of this finding is complicated by the fact that racemic ketamine comprises 50% (S)-ketamine. " < huhwaitwhut? yes, yes it does. "complicated"?
this is nuts. Ide and Ikeda 2018 "However, recent reports revealed that (R)-ketamine exerts more potent and sustained antidepressant
effects than (S)-ketamine, without causing adverse effects, such as psychotomimetic behavior, neurotoxicity, and abuse
potential, in animal models"
effects than (S)-ketamine, without causing adverse effects, such as psychotomimetic behavior, neurotoxicity, and abuse
potential, in animal models"
but wait! "Yang et al. report the antidepressant effects of (R)-norketamine and (S)-norketamine enantiomers—predominant metabolites of (R)-ketamine
and (S)-ketamine enantiomers, respectively—and their mechanistic
targets. ..(S)-norketamine had more potent antidepressant effects"
and (S)-ketamine enantiomers, respectively—and their mechanistic
targets. ..(S)-norketamine had more potent antidepressant effects"
so maybe it was approved as the prodrug? whee!!!!!!
Anyway. It is not impossible that s-ketamine is improved as an antidepressant compared with ~50/50 r-ketamine/s-ketamine (racemic, aka plain old ketamine). But maaaang. We have to be suspicious given the amazing results being obtained with racemic ketamine.
And the sky high costs that will be associated with giving a for profit company this sort of new approval. I wonder if docs can work with compounding pharmacies to get nasal sprays made up?
Ok. So we have a suggestion that you can’t get enough racemate in via nasal spray and so the enhanced potency of stripping it down to the active enantiomer makes all the difference.
The inpatient treatment is iv, I don’t know what the pacing is- quick slam vs slow drip. I thought it was the latter but don’t recall why I think that. You need to do this with cognitive testing to keep levels stable across time
So I may be conflating that methodological issue with antidepressant treatment.
Point being that saying you can’t get enough in with nasal spray needs more elaboration. Why not two paced sniffs?
Why not an inhaler like a bronchodilator for asthma?
Why weren’t NIMH and all the fancy academic scientists pushing hard for the cheapest possible solution instead of cosying up with industry profit seekers?
(And perhaps they were. Willing to be shown wrong here)
https://drugmonkey.scientopia.org/2012/12/11/should-nimh-be-funding-me-too-drug-development/ AZD6765, that was the one I was thinking of before. How is it coming along?
Kevin MD on #esketamine
Esketamine is not a breakthrough new drug: Why the nasal spray for depression is old news https://www.kevinmd.com/blog/2019/03/esketamine-is-not-a-breakthrough-new-drug-why-the-nasal-spray-for-depression-is-old-news.html via @kevinmd
Esketamine is not a breakthrough new drug: Why the nasal spray for depression is old news https://www.kevinmd.com/blog/2019/03/esketamine-is-not-a-breakthrough-new-drug-why-the-nasal-spray-for-depression-is-old-news.html via @kevinmd
Intranasal ketamine has apparently been available for awhile? https://www.resetketamine.com/blog/2019/3/4/5-things-you-need-to-know-about-intranasal-esketamine-for-depression
