First of please understand that all the trial data you read is typically based on a “one size fits all” dose. Unless there is a good side effect reason to vary….don’t vary, take the recommended dose.
Now on to theory.
For every drug there is what is known as a therapeutic index. Making the rash assumption that everyone knows alcohol we see that the theory “if a little is good, more must be better” does not necessarily hold.
Alcohol is a drug and we see three general things:
The first has the technical name “Therapeutic Index”. With alcohol this looks like:
- Low dose – not much happens
- Medium dose – happy
- High dose – punchy, miserable or beer goggles issues
- Overdose – steering the toilet or lying in the gutter unconcious
We also see the second thing called “Tolerance”
- As a teenager a couple of drinks might have got you to medium dose happy
- Push that for a while consistently and your dose requirement might increase to a bottle of wine
- Continue long enough and the bottle will need to be Scotch
We also see the third thing, often disguised by tolerance:
- Small people can’t drink as much and get drunk on less
So how does this relate to real drugs, as in medications?
So given a promising new drug the first task is to work out the therapeutic index.
The phase 1 study of Sofosbuvir might for example of experimented with doses like (for 75 kg average body weight)
- 0.66 mg/kg 50 mg – does not work
- 1.33 mg/kg 100 mg – just works
- 2.66 mg/kg 200 mg – really works
- 5.33 mg/kg 400 mg – really works
- 10.66 mg/kg 800 mg – really works
- 21.33 mg/kg 1600 mg – really works but getting sides
- 42.6 mg/kg 3200 mg – really works unacceptable sides
So on that basis we would decide 200-800mg looks good.
400 mg is best because if that works in a 75 kg person (at 5.33 mg/kg) then a 150 kg person would get 2.66 mg/kg (works) and a 37.5 kg person would get 10.66 mg/kg (works). When the therapeutic index is wide a one dose fits all dose is convenient for manufacturers who then only have to make, and pay for regulatory approval for one dose.
Tolerance to a medication develops for a number of reasons but to keep it simple we will just consider metabolism. You liver has some general purpose garbage collection enzymes (Cytochrome P450). CYP3A4 is one example and helps remove daclatasvir from your system. Our bodies are reasonably clever and run a kind of “just in time” metabolism increasing the levels of garbage collection enzymes in response to need.
By way of example a 50 kg jockey was taking Sof/Dac and still getting sides 2 weeks in. Of his own volition he halved the dose of Dac and the sides went away. At 2/3 dose they came back mildly and at 3/4 dose more. Worried about not taking the full dose he gradually got back to the full 60 mg dose over time – being able to do this probably represented the development of tolerance.
