Dosage studies happens between Phase 2 and Phase 3 trials (and Phase 4 "post marketing" too) and are the most expensive, longest and most scientific process that arguably any business engages in in the entire world.
Phase 1 is a safety test in healthy ~men. These seek to find the maximum dose before adverse effects appear in the healthiest humans.
Phase 2 is a safety/dosage test in a much larger and varied sample. We know dose ranges and begin testing them for efficacy in a varied population.
Phase 3 is the big one. It's a randomized, controlled, double blind test of SPECIFIC dosages in SPECIFIC target populations to scientifically prove efficacy over placebo.
The dose we take is not a "BEST GUESS"
It is the result of a billion dollars of scientific study and that PRECISE NME (new molecular entity) has been studied, at that PRECISE dose, in a target population, for it's effectiveness, and it must be better than existing-treatments and better than placebo.
It should be highlighted that this process takes on average 10 years, costs $1 billion dollars, and has a success rate (success meaning FDA approval) of about 1 in 10,000 attempts (hence the price tag).
Source: Drugs: From Discovery to Approval, Second Edition http://onlinelibrary.wiley.com/book/10.1002/9780470403587
https://www.ncbi.nlm.nih.gov/pubmed/14714120 No difference in response between people taking 20 mg prozac daily vs. every third day.
Edit: The $1 billion number is meaningless outside the context of large pharmaceutical companies. The cost for phase 3 trials is in the tens or hundreds of millions of dollars so the floor is a wide range and there have been instances of companies getting incredibly lucky and developing a drug for much less than a full billion.
You are the one who is completely wrong.
The dosages most certainly do start out with a "best guess" in the pre-clinical phase. For any given drug we would guess at the doses based on our calculations, and give a range on either end. If we thought the effective dose would be 1 mg/kg, we would run an LD50 of doses much higher than that, 10mg/kg, 100mg/kg. Sometimes our guesses would be wrong, and the low dose animals would die as a result. After figuring out a safe dose, we would then split it further into different dosing groups to test the effectiveness of the compound. Most people in the field are underpaid, overworked, and do sloppy work
Please talk to someone who has actually worked in the Pharma research field, they will tell you most of what they do is just guessing.. why do you think only 1 in 10,000 make it through?
It's all a guess until the end, and even then we're often not sure. Look at anti-depressants. We still don't know how a lot of those work but prescribe them to millions of people regardless. How do you think they determined the dose when they don't know how the drug works?
Hence the 'The dose we take is not a "BEST GUESS"' (emphasis mine). Unless you're a lab animal or a person in a clinical trial, the does you take is the end result of lots of money spent on first figuring out maximum safe dosages (Phase 1) to prescribing guidelines that doctors are taught (Phase 3).
Antidepressants are a unique group of drugs because the dosage is highly dependent on each person's unique brain chemistry and a huge part of a good psychiatrist's job is working with their patients to find the right dosage and combination. The problem is that many psychiatrists don't have the time (due to insurance billing practices) or the patience to do the work but any decent psychiatrist will tell you that recommended doses for antidepressants are just a safe starting point for most patients, not the dosage that they will eventually find most effective.
For the record, I have worked in the pharmaceutical industry on pre-clinical drug development and Phase 1-3 marketing applications and the GP's description is largely accurate whereas you seem to have a chip on your shoulder. I wouldn't trust a single book about the drug development process that wasn't heavily influenced by the pharmaceutical industry in one way or another just like I wouldn't trust anyone without semiconductor industry experience when talking about Intel's cutting edge fabrication processes.
How does one accomplish this absent trial and error?
This fact undermines the entirety of your argument.
"Best guess" is exactly what they do.
Please take your clearly ignorant bias and anti-pharma prejudice somewhere else - you have no idea what you're talking about.
We know how antidepressants work, the chemical reaction is well known and can be quantified at different doses. We just don't know why they work because we don't understand why/how the brain works.
Pedantic but important difference.
I have a prescription for dexamphetamine, but I don't use/need it a lot, so I have some bottles left that are a bit old--not past the expiration date, which appears to be slightly less than 3 years (after the date of the recipe), on the bottle I'm currently looking at. So I was curious about the amphetamines in particular, and if it's just efficacy deteriorating a bit that's fine, because in my personal experience the effect (which is quickly and clearly noticeable) varies easily by 25% already, depending on so many other factors (like what/how much I eat, how well I slept, stuff like that).
10-25 percent of....what?
Wrong. Therapeutic ratio, not dosage.
LSD's therapeutic index is unknown because its LD50 has never been established in humans or monkeys and you can't extrapolate from non-primate animals to humans (for example, rats can handle a dose of fentanyl that is a thousand times higher per kg than monkeys can, which is where many of our LD50 estimates come from).
I was going to post something long about LSD but it turns out I am just wrong. So thanks twice, and have my upvote.
Likewise, in a clinical setting (i.e, with a trained anesthesiologist in fentanyl's case), the dose at which 50% of patients die from a given drug is usually much higher because trained professionals can quickly receive feedback by monitoring the patient's symptoms and apply drugs or medical devices to keep them alive well beyond what could kill someone on the street.
The therapeutic index is the ratio of the therapeutic dose to the dose at which the drug starts becoming toxic in 50% of the sample. I repeat, for the third time, I was not talking about toxicity. We are discussing drug expiration dates and you will not experience toxicity from a drug that has been degraded over time to a dosage lower than the one you were prescribed, except in extremely rare circumstances. A drug's therapeutic index is entirely irrelevant to what I am talking about - I don't know how I can make that any more clear.
It also does not follow that because a drug is active in small amounts, i.e. micrograms instead of milligrams, that a small percent change in the dosage will be more important. Full stop illogical, and also not true in practice.
So yes, I'm not a doctor and I don't know the jargon. And when I read your comment I forgot the article was about expiration dates, i.e. percent decrease. And yet you were still wrong on that particular point.
In my personal experience (a decade of Burning man), when you do have a known concentration of liquid LSD (measured with an LCMS) that you carefully handle, store, and dilute for dosages, 100 mcg and 125 mcg can mean the difference between a good trip and a bad one in at least a tenth of my sample size and can drastically change the intensity of hallucinations (going from zero to fractal visuals to aliens) in a good quarter - not to mention the effect on the body high and introspection. If you're buying tabs, the chances that you are even close to the original concentration falls rapidly the further removed you are from the original source. Most people can't tell the difference between a 100mcg and 125mcg tab because those dosages are exaggerated and many people feel stereotypical effects at lower dosages. You can easily test this by eating a significant fraction of a blotter: you are extremely unlikely to experience the effects described by the literature of 50 ng/mL blood concentrations even if you're lucky enough to get to 5 ng/mL effects with a few tabs.
Saying that a 25% change is more significant for more potent drugs is illogical on the face of it, because a % is a dimensionless quantity. If there is some subtle reason why this trend exists I'd love to hear it.
Actually, the reverse is illogical because few biochemical systems have linear responses, especially when you're talking about something as complicated as the neurotransmitter systems that LSD effects. Potency depends on two factors: the affinity of the drug, or how well it binds to its target receptors, and efficacy, or the relationship between the concentration of the drug (and second order neurotransmitters) and the ability of the receptors to initiate a cellular response. Neither of those two factors are linear and they both change as the concentrations of the drug and its byproducts change. As neuron receptors are activated by LSD, they cause cells to release a flood of other neurotransmitters at varying concentrations (dependent on LSD concentration and individual brain chemistry) that start interacting in complex ways like preventing the LSD and other neurotransmitters from binding as effectively (lowering their affinity), potentiating the cellular response (increasing its strength aka increasing efficacy), or building tolerance (lowering efficacy due to exposure). Each receptor and neurotransmitter pair behaves differently. Neurotransmitters in general can't activate cellular responses before they are above a threshold potential that causes the neuron to react, after which the cellular response is never linear. A 2x increase in concentration will rarely achieve a 2x response unless it falls in a small range where the curve is mostly linear, and even then the complex interactions between all of the neurotransmitters will usually compound into a nonlinear response anyway.
These interactions get so complicated, for example, that you get many cases were an opiate A, which is technically 10x more potent than an opiate B, can actually be less potent at treating mild pain because it has a steep response curve that doesn't ramp up until a certain dose. 10mcg/kg of opiate B might be 10x stronger than 10mcg/kg of opiate A (which could be too low to even feel the painkilling effects of opiate A) but once you hit 50mcg/kg concentrations, opiate A might be 10x more potent than opiate B, whose effects plateau with doses higher than 20mcg/kg. Potency is typically expressed as the [A]50 - the concentration of the drug at which you reach 50% of the maximum effect, which depends on the therapeutic effect you're looking for. So in this example, the [A]50 of opiate A in mild pain scenarios can be 25mcg/kg versus opiate B's 7 mcg/kg while with severe pain, the [A]50 of opiate B can be above its LD50 and opiate A's can be 30 mcg/kg because from 25 to 30 mcg/kg opiate A has an exponential response curve. Like I said, it's very complicated and when measuring potency, you're actually measuring the effects of concentration on "arbitrary units," which could be something concrete like a chemo drug's effectiveness at killing cancer cells or something subjective like pain relief. When it's the latter, especially, potency has a very specific meaning in pharmacology that is very different from how the word is used colloquially.
Please don't talk about pharmacology. Period. You don't know what you are talking about and someone might make the mistake of believing otherwise and do something dangerous.
> There are a few compounds (like fentanyl or LSD) where the dosages are so small and the compound so potent that 10-25% makes a difference but for the majority, precision isn't that critical.
As in, typical dosages for fent or LSD are on the order of micrograms, so we expect them to be sensitive to a 25% change, for other drugs where a typical dose is measured in mg or grams, 25% is less likely to be a big deal, etc. This is the only way to interpret what you wrote, and it doesn't make sense. No such trend exists. None of the "basic facts" which you "explained" above (which I already knew) go anywhere near supporting this assertion.
Put another way, if you know the [A]50 you know one point on the dose-response curve, but in general that tells you nothing about the slope or shape of the curve near that point.
Judging from your comment history, you are not an actual doctor or biomed researcher, just a programmer in that industry. Which makes your teeth-gnashing about what an authority you are a tad less persuasive.
The only drugs that weren't within 10% of their original concentrations, according to the study, were amphetamines and aspirin. I can't think of any uses off the top of my head for those two where even 25% would make much of a difference to outcomes - amphetamines are mostly used as general purpose stimulants or to treat ADD and aspirin is not the blood thinner of choice for life and death situations. With amphetamines especially, what you eat and small factors like blood pH can have a massive impact on their effectiveness so we're already talking 10-20% differences day by day, let alone person to person.