Cmax, Cmean, and bears, oh my?

October 30, 2018 9:16 AM

Suppose there is a drug with a 28 day half life. It's prescribed as 2 units every 28 days, and has a 28 day half life. Other than patient compliance, are there sound pharmacological / pharmacokinetic reasons to prescribe it that way, rather than 1 unit every 14 days?

The resulting serum concentrations look like this. I suppose the real question is - are there cases where it's really C_max that matters most?

posted by dmd to Science & Nature (11 answers total)

Is the drug 100% bioavailable? If it is taken orally/nasally/rectally/any way other than IV, probably not. Oral's the worst because of first-pass metabolism (except in the case of drugs that work directly in the gut, like PO vancomycin for C diff.) Depending on bioavailability, you might need more units to actually achieve your desired area under the curve.
posted by basalganglia at 9:31 AM on October 30, 2018

Response by poster: For the specific case i’m interested in it’s injected in thigh or abdomen.
posted by dmd at 9:42 AM on October 30, 2018

Because of the way half-lives work, you will always have less of the drug in your blood with twice-a-month dosing than with once-a-month dosing.
posted by ubiquity at 9:53 AM on October 30, 2018

Response by poster: Sorry to threadsit, but ubiquity - that's not true. Half the time you'll have more, half the time you'll have less (see the graph I included in my question).
posted by dmd at 10:13 AM on October 30, 2018

I wonder it could be related to how the body responds to the medication, not just the level of the medication in the body. For example, the high dose might better trigger a positive response in the system that stays elevated for a period after the dose level falls while a moderate dose might not trigger a therapeutic response. Or, in the opposite direction, a high dose might wipe out something that gradually takes time to build back to a symptomatic level while the moderate dose might never get the thing low enough to eliminate symptoms.
posted by metahawk at 10:34 AM on October 30, 2018 [2 favorites]

Your description is similar to the change in dosing that took place about 20 years ago with a class of injections called aminoglycosides. Initially, this drug was given 3 times a day but there was a shift to once daily dosing where a much higher dose was given once a day instead of a smaller dose given 3 times a day.
I believe this change was due to reduce risk of toxicity. I seem to remember that toxicity was related to time above a certain concentration. When the drug was given more frequently, the concentration did not drop below toxicity level. With the larger interval between administration, the body was able to clear the drug below the toxicity level before the next dose.
Also, the effect of this drug was concentration dependent (antibiotic), so the once daily dosing was not only safer but more effective also.
posted by drug_dealer73 at 11:02 AM on October 30, 2018 [3 favorites]

Narrow therapeutic index? If you tend to start getting bad side effects not very far above the therapeutic dose, then dosing more frequently means you can keep the maximum dose lower. On preview, this is the "term of art" for the phenomenon drug_dealer73 is (eponysterically) talking about.
posted by en forme de poire at 11:05 AM on October 30, 2018 [3 favorites]

I don’t have any formal training in drug dosage, but I have lots of training in nonlinear dynamics, and metahawk’s point rings true to me. In complex systems, critical thresholds and other forms of threshold dynamics are fairly ubiquitous.

Sure enough, a quick search on google scholar for /dose response critical threshold/ turns of lots of research indicating this occurs in drugs too. Eg here, but I’m sure you can find plenty more examples using that terminology.

I have no idea how often this would be a reason to prefer the former over the latter of your dose examples, but it seems to be a real thing that happens, and in that case the c_max absolutely matters as much or more than mean concentration over a week.
posted by SaltySalticid at 11:09 AM on October 30, 2018

You might look up the history of the drug label. The labels often discuss the studies which helped determine safety, efficacy and dosing. There’s usually a reason for the dosing.
posted by Riverine at 2:29 PM on October 30, 2018

I'm a pharmacist and I remember learning about the example drug_dealer73 gave when I was in school. The fact that high-dose once-daily gentamicin or tobramycin actually worked better than low doses given 3 times/day was really unusual. I can't remember any other drugs that work like this. I mean, in general you want to give drugs as infrequently as you can get away with. In your example, giving the drug every 14 days instead of every 28 days means twice as many chances to have an injection site reaction, twice as many refills to pick up at the pharmacy, twice as many syringes and needles to have to dispose of, etc.
posted by selfmedicating at 6:47 PM on October 30, 2018 [1 favorite]

Here's a nice review of this phenomenon with aminoglycosides:

Clinical studies have demonstrated that achievement of high peak serum concentrations of the aminoglycoside ... may be a major determinant of the clinical response to the aminoglycosides. ... In addition to concentration-dependent killing, aminoglycosides also demonstrate a property known as the postantibiotic effect, which may be defined as a period of time after complete removal of the antibiotic during which there is no growth of the target organism.

There is also saturation kinetics with regard to toxicity so that "Less frequent dosing of aminoglycosides allows for serum concentrations of the drug to fall well below the threshold for binding to tissue receptors"

These two effects seem to favor less frequent dosing.
posted by exogenous at 7:04 AM on October 31, 2018