The issue of clarithromycin and increased cardiac deaths #4 - Where are the potential sources of variability?

1. Bioavailability
Regardless of its touted lipophilicity, clarithromycin has a reported average bioavailability of only about 50%. Generally, as a guiding principle, the lower the bioavailability, the greater the potential for variability in systemic availability.

2. Uncertain target site concentrations
There are two associated problems here.

Firstly, clarithromycin has an elimination half life of about 3-5 hours at low doses and 5-7 at higher doses. At a 12 hourly dosing intervals, there will be significant fluctuations in the plasma concentration profile. Even if it is administered at 8 hourly intervals, and if half-life is assumed to be at the high end of the range, say 8 hours, there will be at least a 2 fold fluctuation between peaks and trough. While this may meet the needs of anti-bacterial efficacy (assuming we keep trough levels above MIC), the levels of the peaks may predispose to cardiac toxicity if it is able to inhibit HERG potassium channels. To some extent, we can mitigate the fluctuations by using extended release formulations, but this may be at the expense of even more variability in bioavailability.

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Comparison between normal formulation and extended release formulations

Secondly, since we do not routinely measure either plasma or tissue concentrations, we have little idea if adequate concentrations are being achieved at the target site. Here, there is some more uncertainty. Tissue and cellular concentrations tend to be higher than plasma unbound concentrations, but concentrations in the extra-cellular fluid (where the bugs are) are variable and may be lower than unbound concentrations of clarithromycin. These are functions of variable protein binding and the variable net activities of specific influx and efflux membrane transporters.

Consequent upon the previous two points, the differential effects of clarithromycin on the bacteria and on HERG channels may be variable between individuals not only because they relate to different effect compartments but the latter may relate to heights of the peak while the former to trough concentrations being above the MIC.

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Relationship between QT prolongation ad clarithromycin concentrations

Although the IC50 for clarithromycin on the HERG channel is about a 100 times higher than the MIC, arrhythmic risk is associated with lower extent of inhibition. Hence cardiac risk is seen at much lower IC10 or IC20 concentrations

Added to all these, is the uncertainty contributed by an active 14-OH metabolite of clarithromycin.

3. Inter-individual variability in pharmacokinetics
Clarithromycin is both a substrate and inhibitor of CYP3A4. This metabolic pathway is also responsible to generating the active 14-OH metabolite. Variable CYP3A4 activity therefore results in a variable mix of clarithromycin and its active 14-OH metabolite.

There is a very high extent of variabilty in CYP3A4 activity in any population studied. There are also significant differences in activity between men and women (women generally higher). While there are genetic polymorphisms associated with CYP3A4, no single genetic variant has been able to account for the variability within a population. On the other hand, CYP3A4 is also vulnerable to many food and drug interactions.

To make matters more complicated, clarithromycin inhibits its own metabolism by CYP3A4, and exhibits a non-linear pharmacokinetic profile.

4. Inter-individual variability in susceptibility to QT prolongation
The HERG potassium channel gene is genetically polymorphic and variants may predispose to variable susceptibility to QT prolongation. Added to this is the uncertainty about appropriate dosing regiments between different ethnic populations, who may have different body weights and distributional volumes, as well as different exposures to CYP3A4 food and drug interactions.

5. Variability in microbial susceptibility
Apart from differences in anti-microbial efficacy due to variability in drug permeation to target sites, bacteria do differ in how susceptible they are to concentrations of clarithromycin. While sensitive bacteria generally have MICs in easily achievable range, resistance genes have become more prevalent and differences in bacterial sensitivity has become more common.

6. Compliance issues
One must never forget the variability that may be caused by failure of the patient to medicate according to instructions, leading to highly irregular dosing intervals and therefore variable degree of fluctuations in circulating drug concentrations.


Taking all these uncertainties into consideration, the question is how to ensure the patient gets optimal dosing? Think about it.

[To be continued]

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)

The issue of clarithromycin and increased cardiac deaths #2 - Pharmacology

Clarithromycin is a macrolide bacteriostatic antimicrobial that came onto the market in 1991. It enjoyed considerable success as an orally administrable macrolide, being relatively lipophilic and having a slightly longer elimination half-life. Came off patent about 10 years ago.

It acts by inhibiting bacterial protein synthesis by blocking the ribosomal RNA. Resistance develops as bacteria acquire various resistance genes, such as the plasmid erm (A) gene that confers an ability to methylate the adenine in the binding site.

Clarithromycin can be administered orally with a bioavailability of about 50%. Its permeability across biological membranes is only due in part to its lipophilicity. A significant part of the process depends on a complex interplay between influx and efflux transporters expressed on various membranes. Consequently intra-cellular, and tissue concentrations do not correlate with circulating unbound drug concentrations. Interestingly, tissue interstitial fluid concentrations are lower than free drug concentrations in plasma, but intra-cellular concentrations are to a variably extent much higher than plasma free concentrations.

The protein binding of clarithromycin is about 60-70%. The Volume of Distribution is about 10 L/kg, which is consistent with significant permeability into tissues. Again this increased permeability results not only from lipophilicity but from the complex interplay of influx and efflux transporters, in this case clearly favouring influx.

Clarithromycin is eliminated by both hepatic metabolism and renal elimination. It is extensively metabolized by CYP3A4 (which it also inhibits), to a principal metabolite 14-(R) hydroxyclarithromycin, which is also pharmacologically (less) active. The pharmacokinetics is not linear, and the elimination half-life increases from 3-5 hours at lower doses, to 5-7 hours at higher doses. Tissue concentrations persist for much longer.

Clarithromycin produces a range of adverse reactions, but the one that concerns us for this discussion is with respect to cardiac death. Like many of the macrolides, clarithromycin has an effect on the myocardial delayed potassium rectifier current, leading a prolongation of the QT interval of the ECG. This prolongation of the QT interval is associated with risk of torsades de pointe and a fatal ventricular arrhythmia.

The usual adult dosage is 250-500 mg 12 hourly for 7-14 days.

Clarithromycin is a drug with very interesting pharmacological properties. Give a thought as to how these properties contribute to variability in the clinical response and the risk-benefit ratio particularly with respect to the problem of cardiac death.

(To be continued)

The issue of clarithromycin and increased cardiac deaths

Just this last week I was discussing with my students, the various factors contributing to variable drug response, and possible differences in the risk-benefit ratios for the same drug in different individuals. The recent publicity about increased cardiac death risks associated with clarithromycin provides a useful case study for many of these issues. Follow these posts for a discussion about this interesting issue.

The original publication about this can be found here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138354/

Essentially, this Danish study looked at a large sample (n=160,297) of patients treated with a 7-day course of clarithromycin. The control groups were patients who been treated with roxithromycin and penicillin V. They found an excess of 37 deaths per million doses of clarithromycin compared to penicillinV. This is a very small though statistically significant increase in risk. The risk appeared to be contributed largely by an increased risk primarily among women. No increased risk was observed for roxithromycin.

As in many epidemiological studies of this sort, the design is far from perfect and there are always ways to cast doubt on the significance of the findings. It is not necessary for this discussion to arbitrate on this matter. Rather, this report serve as a context for us to consider the various mechanisms that may contribute to inter-individual variability in the risk-benefit ratio for a drug such as clarithromycin.

(To be continued)