The issue of clarithromycin and increased cardiac deaths #3 - Does the usual dose or concentration-response relationship apply clinically?

Very often students are taught models of the dose- or concentration response relationship that do not seem to apply clinically. This is because the traditional model of that relationship was derived from in-vitro experiments, and based on the early experiments using G-protein coupled receptor systems. Invariably these receptor systems were superficially sited on the membranes of effector cells. In the simplest of these models the binding of ligand to the receptor is reversible and competitive.

For clarithromycin however, the drug acts by the inhibition of ribosomal RNA within microbial cells. While this binding to the 50S sub-unit of the ribosome may be reversible, the effects are not. Unless the bacteria carries resistance genes, the bacteria either stop growing or dies. So the concentration-response relationship must incorporate elements of growth, death and resistance. Even so, the model will only work if we know the intra-cellular concentrations of clarithromycin. And we do not know that. For clarithromycin, we are ignorant of not only intra-microbial concentrations of the drug, but we are also not even sure of the concentrations of the drug in the fluids bathing the bacterium. We only see plasma concentrations. Unbound drug concentrations in the plasma vary between individuals, and have an unpredictable relationship with interstitial fluid concentrations.

Taking all these into consideration, it is clear that we will not be able to construct any meaningful concentration response relationship according to the traditional model. Instead, we have a model of drug response that is based on the minimum inhibitory concentrations (MIC). For S. pneumoniae, the clarithromycin sensitivity breakpoint occurs at approximately 0.25 ug/ml. Correspondingly, clinical efficacy will depend on how much of the concentration time profile sits above this concentration. More, correctly though, this refers to the concentration in the interstitial fluid, and we can only guess-timate this from plasma concentrations.

Another complication is the fact that, clarithromycin is not the only active molecule against Gram-positive bacteria. The main 14-OH metabolite has activity, albeit lower. Hence, concentrations of clarithromycin alone will under-estimate the anti-bacterial effect.

There is of course, a flip side of this story that has to do with the cardiac toxicity. Macrolides such as clarithromycin have effects of the cardiac HERG potassium channel, leading an inhibition of the delayed rectifier potassium current during the cardiac action potential. This results in a prolongation of the QT interval of the electrocardiogram, which predisposes to potentially fatal ventricular arrhythmias such as torsades de pointes. The concentration response relationship for this effect is quite different from that discussed above for antibacterial effect. The IC50 for clarithromycin on the HERG channel is approximately 30 ug/ml which is about 100 times higher than the MIC.

This therefore sets a therapeutic window for the use of clarithromycin where the physician would need to ensure that clarithromycin concentrations in the inter-cellular space will be higher than the MIC but not so high as to inhibit the HERG channel.

Think about how we best can do this. See this in the context of the Danish study where there was an excess of 37 cardiac deaths per million doses.

(To be continued)