Area under the curve in a drug concentration curve

Question

I am not from a background on pharamacokinetics and trying to learn some concepts.

I noticed that the definition for AUC involve the first 24 hours. For example in here AUC is defined as "the area under the concentration–time curve over 24 h divided by the MIC."

• Is there any reason why this 24 hours is selected?
• Say I test 2 treatment strategies. Strategy 1: 500 mg tablets given 3 times a day (500m g×3, 8 hours apart) and Strategy 2: 500 mg tablets given 3 times a day for 2 days (500 mg×6, 8 hours apart). In this case if I simulate the change in the drug concentration over time assuming exponential decay, then the two concentration curves would have the same values for the first 24 hours. Therefore the AUC obtained in the first 24 hours for these two strategies are the same. But strategy 2 performs better than strategy 1. So, in this case isn't the total area under the curve above MIC a better index than consdiering AUC in the first 24 hours?
• Is it wrong to inform why a particular dosing strategy is effective than the other one using 'Total area under the curve (rather than of the first 24 hours)'?

Answer 1

This definition of AUC is non-standard.

The usual definition does not involve the MIC or 24h: it is the area (~ integral) of the plasma concentration curve as a function of time, from first administration time $t_0$ time to infinity. (You will sometimes see it subscripted as $\mathrm{AUC}_{0 \to \infty}$)

In the case of so-called time dependant antimicrobials (beta-lactams, macrolides, vancomycin), the bacteria are inhibited from replicating as long as the concentration stays above the MIC (minimal inhibitory concentration). Often a second threshold, the MBC (minimal bactericidal concentration) is defined corresponding to the required concentration to kill rather than just inhibit replication.

As you stated, the second strategy has indeed a longer duration above MIC. It is more effective from a purely kinetic standpoint. Whether than translate to clinically relevant effects depends on the antibiotics, the bacteria and the tissue under consideration.

A second point is whether a higher AUC is beneficial if the time spent above MIC or MBC is the same (nb: not the case here). However this also depends on factors beyond just pharmacokinetics.

As an aside, some antimicrobials like the aminoglycosides display a "concentration dependant" effect where the peak drug concentration determines the effect, dictating different dosing schedules.