[HN Gopher] Pharmacokinetics: Drug development's broken stair
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Pharmacokinetics: Drug development's broken stair
Author : Ariarule
Score : 52 points
Date : 2023-09-30 19:26 UTC (3 hours ago)
(HTM) web link (trevorklee.substack.com)
(TXT) w3m dump (trevorklee.substack.com)
| gumby wrote:
| Yes, pharma is empirical, not predictive. We are very far from
| understanding biology well enough to be predictive (except on
| TV).
|
| Look are Loewe's recent column in Science: Target-based drug
| programs seem like an obviously sensible approach but in practice
| have not been fruitful: https://www.science.org/content/blog-
| post/target-based-drug-...
|
| Biology is still art and luck.
|
| Note: I'm a former small molecule pharma developer myself.
| snitty wrote:
| >We are very far from understanding biology well enough to be
| predictive (except on TV)
|
| I'm very excited for the next season of Small Drug Discovery on
| NBC. I hear the first 5 episodes this season are just screening
| candidates.
| foota wrote:
| I think the finale will cover a phase 1 trial!
| User23 wrote:
| One of the most wildly productive periods in small molecule
| drug discovery was back when crazy, mostly German, chemists
| would taste their products as part of characterizing them.
|
| That's why, among other things, we have such wonderfully high
| quality data on progressive mercury poisoning.
| gumby wrote:
| Saccharin was discovered when Ramsen rolled a cigarette and
| noticed that the paper tasted sweet (there is a non-tobacco
| version of this for the faint of heart).
|
| And Alexander Fleming discovered penicillin because some
| bread from an old sandwich did not become moldy.
|
| Modern lab procedures preclude any such discovery today.
| vonnik wrote:
| > We could fix this stair. It would just require the raw data
| from a variety of pharmacokinetic trials, some in-depth
| experiments on human liver and gastric membranes, and some
| simulation of the physics of how different drugs diffuse into the
| bloodstream and across membranes.
|
| This statement seems overly optimistic. Predictive
| Pharmacokinetics that obviates most trials would need to model
| all possible drugs for all people. The computational complexity
| of that problem seems out of reach. The best way to get to know
| complex adaptive systems (which can't be properly simulated most
| of the time) is to test them empirically.
| NicotineFiend wrote:
| I'm surprised the article didn't mention anything about
| pharmacogenetics. For example, drug-metabolizing enzyme
| polymorphisms can often lead to a 10+ fold difference in Cmax (or
| name the parameter) between a poor and an ultrarapid metabolizer
| of some enzyme.
| klevertree wrote:
| Author here. Enzyme polymorphisms are tricky and would require
| a whole different blog post. Some drugs they matter a lot for,
| some drugs they do not. I actually have not found any drugs
| with 10-fold variability that could be ascribed solely (or even
| mainly) to polymorphisms, although it doesn't seem impossible.
| opportune wrote:
| https://www.ncbi.nlm.nih.gov/books/NBK84174/
|
| Here's an article I found in 30s of searching (granted, I
| already knew Warfarin was hugely affected by CYP2D6) stating
| that equivalent maintenance doses of Warfarin can vary by a
| factor of >10 (from 0.5mg to 7mg) based on the CYP2D6
| phenotype of the patient.
| 303uru wrote:
| What drug has a 10 fold difference in Cmax, as a pharmacist I
| can't think of anything even close to that.
| opportune wrote:
| Warfarin is one of the most well known scientifically, but as
| a practitioner you may not know this because hospitals and
| insurers are scared to acknowledge the ongoing rate of
| preventable bad outcomes caused by _not_ accounting for
| variances in metabolism.
|
| That is to say, if we were to actually start assessing
| patients' ability to metabolize warfarin we'd have to
| confront the fact that a huge number of bad clinical outcomes
| in the recent past stemmed from not doing this.
| carbocation wrote:
| > _hospitals and insurers are scared to acknowledge the
| ongoing rate of preventable bad outcomes caused by not
| accounting for variances in metabolism._
|
| Healthcare systems are so aware of and open about
| warfarin's risks that they have warfarin clinics set up to
| repeatedly measure patients' prothrombin times so that they
| can adjust dosing empirically. Further, they also provide
| nutritional guidance to patients taking warfarin to help
| them reduce diet-influenced variance in warfarin
| metabolism.
| scheme271 wrote:
| What about codeine with ultra-rapid metabolizers (e.g. the
| significant population in Saudi Arabia), it might not be a
| 10x difference but normal dosages can result in overdose or
| death in people that are ultra-rapid metabolizers or even in
| their babies if they are nursing mothers.
| NicotineFiend wrote:
| Many tricyclic antidepressants metabolized by CYP2D6 would be
| here, if you put the nonmetabolizers up against the rapid
| metabolizer, https://en.wikipedia.org/wiki/Doxepin for
| example.
| klevertree wrote:
| Cyclosporine and tacrolimus, if you look at the range in any
| of their pk trials you'll easily see 10 fold variability.
| marcosfelt wrote:
| There's a company called VeriSIM life trying to make the
| physiological models mentioned in the post more accessible [1].
| They apparently fit their models across a bunch of publicly
| available and proprietary data. I found some peer-reviewed
| publications (e.g. [2]), but I am not sure how widely they are
| used.
|
| [1] https://www.verisimlife.com/our-platform [2]
| https://www.tandfonline.com/doi/full/10.2147/DDDT.S253064?ro...
| cowsandmilk wrote:
| Simulations Plus has been building models on this data since
| 1996 and is one of the more popular vendors for prebuilt
| software for this modeling. There's literally dozens of vendors
| with software though because companies have been working on
| this since the 80's despite the article's claim that this has
| been an ignored problem.
|
| https://en.m.wikipedia.org/wiki/Simulations_Plus
| jrflowers wrote:
| I like how the author has discovered that a problem that costs
| pharma companies billions of dollars actually has a quick fix:
| simply model how livers react to infinite compounds.
|
| Since all livers behave the same and there is no variation based
| on gene expression or disease, this is a trivial task! The reason
| why this hasn't been Solved is because none have been Disruptive
| enough to dream of doing research in this area.
| radus wrote:
| Moreover, pharma companies and academics already do model PK..
| it's a huge field of study, not some ignored "broken stair" -
| there is definitely "serious money" behind this.
| klevertree wrote:
| Author here. That's not what I said. Please don't be a jerk on
| the Internet.
| jrflowers wrote:
| You literally wrote
|
| > It would just require the raw data from a variety of
| pharmacokinetic trials, some in-depth experiments on human
| liver and gastric membranes, and some simulation of the
| physics of how different drugs diffuse into the bloodstream
| and across membranes. This would be difficult, but not
| impossible, and would not require any huge scientific
| advances.
| cowsandmilk wrote:
| As someone who has worked in pharma, this article is pretty damn
| ignorant. There's a ton of funding for pharmacokinetics work. For
| liver and the gut, it is widely agreed that 2-D tissue culture is
| completely non-predictive, so the last couple of decades have
| been building 3-D tissue culture and nowadays, companies
| commercially purchase organs on a chip for both and even multi-
| organ systems[0]. Plenty of companies have internal teams that
| have built similar technology and they all have teams working
| hard trying to build computational models on the generated data.
| But small changes in molecules have huge ADMET impacts and these
| organs are just a subset of the organs that can impact
| pharmacokinetics. Plus, toxicology can tank a drug by impacts on
| nearly any organ, so whole animal models always still win.
|
| The entire article just yells ignorance of what drug companies
| work on and what they're investing in.
|
| [0] https://cn-bio.com/models/
| klevertree wrote:
| Author here. As someone who works in pharma, organ on a chip
| models are not even close to being relevant to providing
| accurate PK curves for oral absorption. The state of the art is
| trying to make it work for cutaneous absorption and that's
| still not great/commercially useful.
|
| My whole point is that there needs to be way more open data on
| pharmacokinetics. That's the only way we're going to solve
| this.
| snitty wrote:
| This is very interesting, and I think massively underestimates
| the variability in how small molecular drugs are affected by the
| body. Small differences in molecules can have drastic effects on
| where, how, and how quickly they're adsorbed, and what systems
| they affect.
|
| More than anything, I think this just underestimates the
| unpredictability of it all. To extend the author's metaphor, if
| you measure the 100 data points from shooting 10 different
| projectiles out of 10 different devices, on 10 different
| celestial bodies, you're still not going to have a lot of
| predictive power that can be generalized.
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