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Yea we have a toxicology report thats what im trying to get a guess of what dose it is.

A single sample? No. Multiple samples? It depends. When dosed, the concentration in blood rises for a period and then declines as it is metabolized and cleared from the body. Each drug has a sort characteristic curve for the drug and it’s metabolites that you could compare to a series of samples taken over time which you may be able to use to determine the initial dose. It depends a bit on the dynamics of the drug clearance, and at what times you took the samples.

The postmortem toxicology report suggests a death of drug overdose, with 0.33ug/ml blood concentration of hydrocodone. So thats what we were trying to estimate.

This interesting paper might help, although I’ve not read more than the abstract. To back calculate how much was taken you’d need a lot more information including time from dose, was it a single dose or taken repeatedly over time as well as height, weight, fat distribution etc

Volume of distribution, time of ingestion, half life of medication, was it taken orally or parenterally, etc, etc, would need to be known.

Also whether this was dose 1 or if there were multiple doses.

But the equations only apply to live people. After death, considerable changes can occur - Some drug concentrations go up, some go down, it’s not exactly predictable.

That being said, I haven’t really used pharmacokinetics and pharmacodynamics for years. Did you ask the person who performed the autopsy?

You need an estimate of when the hydrocodone was taken, and an assumption that it was taken as a single dose. Also need to know the route of administration. Probably oral for hydrocodone. Then google "hydrocodone pharmacokinetics" and compare some graphs. May need to convert units also.

Looks like typical concentrations are around 10-100 ng/mL following normal doses in the 10-60 mg range. A blood concentration of 330 ng/mL is quite high based on very brief research.

Published papers on postmortem concentration in hydrocodone overdose give numbers around 0.4-0.5 mg/L (ug/mL) so overdose sounds plausible here, probably took a dose of >100 mg hydrocodone if I had to guess.

This is not legal or medical advice FYI

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In a criminal justice context, an expert toxicologist's opinion is often in the form of whether the concentration in the blood is "consistent with a therapeutic range."

So, for a given medication, there will be studies that say something like (just some random numbers here) "this medication is usually dispensed in doses of 10mg once per day at the low end and 70mg once per day at the high end. People who take a 10mg dose typically have a blood concentration that peaks between X and 2X after approximately an hour, and people who take a 70mg dose typically have a blood concentration that peaks between 7X and 14X after an hour. The substance in the blood has a typical half-life of 8 to 12 hours. On a daily dose, baseline blood levels will stabilize at Y for 10mg daily and Z for 70mg daily."

So, let's say someone has 80X in their blood. A toxicologist will be able to say with confidence "that's not consistent with a therapeutic dose - this person ingested way more of the substance than a doctor would ever prescribe." So, either drug abuse or poisoning.

Now, say someone has 2X in their blood. A toxicologist can say "that's consistent with a therapeutic dose" - but not much more than that. It's quite possible that person took 10mg or 20mg an hour ago, and takes that every day - but they may have taken 70mg 16 to 24 hours ago as a one-off. Or they may have taken 40mg 12 hours ago, and every other day for the last month. Or they may have taken 1,000mg 48 hours ago.

So, that's some of the nuance: it's fairly easy to rule out certain dosage quantities/timelines, but it's much harder to say what actually did happen. A lot of the time, the first one's all that's needed.

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Very good explanation. Thank you.

Thank you. Yea, and there were also other drugs in the system, specifically diphenhydramine and cyclobenzaprine. I know there's just no way to figure it out. But 100mg of hydrocodone doesnt seem like a lethal dose for a person with tolerance.

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Each person is different, but I happen to know that for a healthy 6’5”, 200lb 27yr old male, who was a moderate opiate addict, a dose of 25 10mg pills (250 mg hydrocodone) taken orally of hydrocodone did not cause overdose. Their were ill effects, but no loss of consciousness and no hospitalization. Again, each person’s chemistry is going to be different, but that did happen.

Sedating drugs can work synergistically as well, so while 100 mg probably wouldn’t be lethal in someone with significant tolerance if you add other sedating meds like diphenhydramine and cyclobenzaprine the overall level of sedation may push them over the edge.

Pretty sure opiate levels continue going down in the blood for a while after death

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Definitely!

Yea

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Adding on to some of the good comments here, many drugs have physical properties that cause them to distribute in body tissues beyond the blood. For instance, when we give patients oral antibiotics for infections of a specific organ (prostatitis, for example), we need to choose an antibiotic that has good penetration to the prostate. Or good bone penetration for osteomyelitis. If a drug is extremely lipophilic and is given to an obese person, the volume of distribution can be effectively limitless and difficult to ascertain, because it distributes beyond the blood and into the fat tissue. The log P value of a drug will give us a clue to how widely the drug distributes, but we would need multiple samples to truly understand the kinetics how the drug is eliminated in a specific patient.

There are also special circumstances that complicate this “2-compartment pharmacokinetics” process. When we give a cancer patient high dose methotrexate infusions, the drug will distribute into any excess body fluid in the patient, like edema. The body will then clear the blood of the drug, but the methotrexate-laden body fluid will effectively re-bolus the patient with the drug and raise their blood levels again, long after we’ve stopped the infusion.

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What’s the age of the person?

100mg is a bit high. Even for someone with tolerance. I personally have never seen a prescription for Norco 10-325 to be taken 10 pills at a time.

But two major concerns present itself:

1. Respiratory depression induced by opioids
2. Liver damage caused by the acetaminophen in the Norco; assuming you are from the US where just getting hydrocodone by itself is not really a thing, minus special cases.

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This is a very exact science called pharmacokinetics. But we need some pretty exact info, like time of the last dose and rough dosing history before that. For most marketed drugs we’ll have a population pharmacokinetic model that we could use to give a prediction interval around a likely concentration for a given dose, or to estimate the most likely dose given an observed concentration.

As most of the answers have said, it depends. When monitoring a patient on certain medications, we will test what is called "peak and trough." Peak is when the medication should be at its highest concentration in the bloodstream, which is typically an hour after dose, although this can vary a little with some drugs. Trough is when the concentration should be at its lowest, which is typically just before the next dose. I believe drug half-life has been mentioned previously, so i wont rehash that. Drug interactions, disease, and things like grapefruit can interfere with drug metabolism rates. Most drugs dosing is calculated using amount of drug/weight of patient/time. Blood volume is assumed. Again, not all drugs are the same, and not all humans react the same, but you could roughly guesstimate the initial dose, which was your actual question. This information isn't terribly useful in most clinical settings. I am a clinical laboratory scientist, so this is a bit of what I do.

For many drugs if you knew the route of administration (orally for example) and the time, you could get a pretty good feeling of the dose.

The pharmacokinetics of drugs give you a curve or a line of some kind and it is possible to back calculate.

There are certain caveats. For some things , the original drug is labile and the metabolite in stable, so you would just measure that. But this is a technical thing, like measuring an oxidized version rather than not. Some things are in bound and free forms and it is technically difficult to get both. Some things have endogenous versions that make it hard to tell what you ate vs what you had (erythropoietin , testosterone) because they are indistinguishable. Some things have such a long or short half life that it becomes complicated. Some things that are stored in fat are tricky to figure out doses of. And all sorts of other little quirks. But , a qualified yes is really the answer.

I did my PhD on this, but for living patients ;)

As you say, there are many factors at play, most importantly distribution volume and drug elimination rate. For all of these factors, you can estimate the typical value and the between-individual variability in the population. We call this a population pharmacokinetic model.

With just a single concentration, you assume this person is a "typical individual". You can back-calculate (based on time of death and time of taking the drug) what the dosage typically could have been. You need the administration time though, the time of death, and you better hope the drug concentration remained stable between time of death and time of autopsy. In clinical studies, blood samples are often stored in solid co2 (-80C), and for good reason.

Using the known variability in the population, you can also give a confidence range for your initial dose prediction. You can make predictions more precise by adding information. Bodyweight influences likely drug distribution volume. A second drug (with known dosage and administration time) could help you too.

Usually, this technique is done for drugs that need to be in a precise concentration range. Give a dose, measure concentration, estimate blood volume and calculate the optimal dose for that patient. We call this Model Informed Precision Dosing: MIPD. You can apply the same in autopsies, but I doubt it is routinely applied. Cool question!

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Is there typically difficulty in getting the specific prescription information from this suspect/victim instead of having to work with all these assumptions?

Is it just coincidence that you referenced the dosage range of Vyvanse? 😂

is this an example of high sensitivity and low specificity? Since you can determine a positive for sure (the 80X example) but can’t determine if the negative is truly a negative or false negative (the latter example)

Kidney/liver issues definitely, but also genetics can affect drug distribution and elimination for many medications (for example, loss or gain of function mutations in drug transporters).

I'd like to see some doctors turn from a punitive and sometimes deadly approach with Vicodin.

I have chronic nerve damage pain, and I had to pressure my otherwise sympathetic doctor, to remove the acetaminophen from my daily dosage.

If they had not done that, I would surely have died by now of liver and kidney failure, over the past decade.

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the problem is that people can have different genes for the expression of drug-metabolizing enzymes.

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So to get any sort of reliable number you would definitely need to know when the drug was ingested. Is this correct?

Aren't you constrained by having tests for all the chemicals in the drug?

Op is describing a case where someone has committed a crime and the police are determining if the amount of drug in their system at the time is abnormally high and would have caused some issues…not like the offender would volunteer they took too much of their painkiller and drove into oncoming traffic

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Somewhat relatedly, how come prescription medicine isn’t sized based on the patient weight?

Surely time is a large factor?

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They do this to make sure the serum is the right level in people who take medications that can change levels based on how long you take it. You need a base number to go off of, so there’s no way to tell exactly how much someone took, but if you’ve tested every month, you’ll know how much that amount will look like in their blood over time. You can tell if someone has overdosed when there’s an amount far greater than a normal dose has entered the system, since it is not longer in the safe therapeutic range and has likely done some damage

In other words, they explain a drugs pharmacokinetics and pharmacodynamics

Correct.

OP is asking the wrong question. Based on what day provided it seems in line with an overdose, especially with the other drugs involved, unless the person was a known addict.

From a tox report you only have a snapshot at the one particular time point. You need multiple time points to even potentially guess the starting dose along with an extensive patient history.

Much needed addition, thank you!

Some drugs are!

Drugs that work with a single dose for everyone are more convenient. Yes, paracetamol 1g tablet may give lower concentrations in someone weighing 140kg vs 70kg, but these drugs are safe and effective over a wide range of concentrations.

Some drugs have a more narrow therapeutic range. We either adapt the dose by bodyweight (paracetamol for children is a prime example!), but can adapt to many many more covariates. Even race can play a role, with some mutations increasing drug metabolism being less prevalent in whites, so more risk of overdose. And sometimes, it is not the dose but the frequency that is adapted (1g 2 times vs 3 times per day)

In some cases, no covariates exist. You either measure concentration in the blood, or you measure the effect (eg drugs for sedating during surgery).

Sure, it would be more optimal to also dose paracetamol that way. Dose high,measure concentration in blood and adapt. You would get faster pain relief with lower risk. But would you come to hospital and pay a team of doctors/engineers to do that, for a simple headache?

That was the question I answered with my PhD: is all that hastle worth it? For some life saving drugs with strong side effects and very variable metabolism, it is.

Yes! In general, you cannot bring a drug to market without being able to measure it in blood reliably. But those tests are often not available in eg a rural hospital. This field is therefore a real interplay between doctors, statistici an/software engineers, and bio-assay manufacturers.

Now for illegal designer drugs, that is a completely different ball game. They may even be built to evade detection.

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To add in, at least in the US it's a little less to do with the therapeutic range and a whole lot more with the safety range,and what was tested during clinical testing.

Since we often look at log differences in the clinic when it comes to safety, you can safely assume for most drugs prescribed at x mg/day that they will still be efficacious in a fairly large range of adult weight ranges.

However, especially with some drugs as you have indicated, this isn't the case. Personally I am often worried with something like hormonal birth control, which we are constantly trying to reduce the dose to limit side effects, however there is efficacy issues with larger patients.

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For a process like this you’d need to have data from studies (like clinical trials) to compare against. You couldn’t a priori take an arbitrary drug and back calculate. For instance, some drugs require a biotransformation to become reactive. Some may be bound and metabolized in a certain organ, and still others may have a short half life.

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As a vet, the question of “why aren’t human medications doses based on weight” has always baffled me! We dose nearly everything in mg/kg because patient sizes are so different. We have some rules of thumb for species with a fairly standard size (mg/cat is a common one!) but I typically double check the mg/kg dose anyway.

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This. Also it would help a lot to know when the dose was taken. Lots of things once they've entered the blood stream are metabolized with sort of a half life. For caffeine, for example, it's about 5.5 hours. If someone has 100mg of caffeine in their system it could be because of the cup of tea they had in the last hour, or the cup of coffee they had six hours ago.

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In humans small differences in weight are usually not that big of a deal. Other factors like liver function or wether you take an oral drug with or without food introduce much more variability. Even if weight varies greatly between subjects, it’s often because of a higher fat mass. Most drugs don’t distribute into fatty tissue that well and so in those cases a weight based dose might over dose someone. Fat free mass is sometimes used but often not really needed. In children we do use a weight based dose though.

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We do this with Wellbutrin in correctional psychiatry. Inmates will sometimes try to abuse this medication to get high (crush, snort, take more than prescribed), and they can also have it stolen or trade it with other inmates. With a random blood draw and a (supposed) time of last administration we can look at the concentrations of both the drug and its metabolite; their ratios give us an accurate picture of what the inmate has taken for the past three days.

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Yes and no.

I'm finishing up a doctorate in pharmacy and the thing is that there are soooo many factors that go into drug blood concentrations. Genes, the drug in question, diet, underlying conditions, kidney function (hard to tell when they are deceased), etc. All play a factor in drug concentrations.

We do however have basic pharmacokinetics diagrams that can apply to a lot of drugs across large populations. Most of the time they are very basic equations though, usually only considering age, weight, height.

There isn't really a perfect answer here.

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