Try and imagine how inter-subject differences in these variables can ultimately affect drug disposition and drug response.
Thursday, August 18, 2016
Visualizing the effects of plasma protein binding, tissue binding and membrane permeability of volume of distribution
The volume of distribution of any drug depends on a number of variables, body weight (affecting absolute physical volume of the tissues), plus the relative affinity of the drug molecule for the tissues. Traditionally the latter has been viewed as being a function of plasma protein binding and tissue binding. Nowadays however, with the increasing appreciation of the importance of membrane transporter proteins in determining permeability into tissue compartments, it is better to view distribution as being affected by a composite variable that emcompasses plasma and tissue binding as well as the net permeability across tissue membrane barriers.
Try and imagine how inter-subject differences in these variables can ultimately affect drug disposition and drug response.Body Weight vs Volume of Distribution
Try and imagine how inter-subject differences in these variables can ultimately affect drug disposition and drug response.
Wednesday, August 10, 2016
Pharmacokinetic variability
Most doctors do not fully appreciate just how much variability there exists in the population with respect to how their patients respond to a standard dose of the drug they use. Even without considering the variability in terms of the pharmacodynamics of the response, there is already a lot of variability.
Here is a simple simulation of what a 'typical' plasma concentration profile might look like after a 8 hourly dosing regimen.
Looks fairly 'normal' doesn't it? But here (below), I have simulated a set of random profiles of a theoretical drug from a fictitious set of 20 patients with a very reasonable range of pharmacokinetic properties (body weight, clearance, volumes of distribution, bioavailability). These are values that one can reasonably expect from any patient. Just look at the wide range of plasma concentration profiles that can be found in a set of 20 'patients'. Whether these are eventually clinically important or not will of course, depend on the specific nature and the toxicity profile of the drug in question, but recognizing that such variability exists, is the first step to being able to personalize therapy.
Looks fairly 'normal' doesn't it? But here (below), I have simulated a set of random profiles of a theoretical drug from a fictitious set of 20 patients with a very reasonable range of pharmacokinetic properties (body weight, clearance, volumes of distribution, bioavailability). These are values that one can reasonably expect from any patient. Just look at the wide range of plasma concentration profiles that can be found in a set of 20 'patients'. Whether these are eventually clinically important or not will of course, depend on the specific nature and the toxicity profile of the drug in question, but recognizing that such variability exists, is the first step to being able to personalize therapy.
Tuesday, September 2, 2014
The issue of clarithromycin and increased cardiac deaths #5 - How can we deal with the variability?
Clinical efficacy is never only about therapeutic efficacy. It is always a balance between benefits and risks. Drug response variability shapes the clinical efficacy curve by altering the relative distance between benefits and risks along the dose or concentration range. Good therapeutics therefore is always about being able to manage the variability in drug response, so that the optimal dose or concentration for the patient can be selected that will maximize benefits and minimize risk.
If we just consider the anti-microbial effects.... we actually manage the variability rather badly. Theoretically, there is a therapeutic target that is based on maintaining drug concentrations at the target site (where the bugs are actually growing) above the minimum inhibitory concentrations (MIC). By drug concentrations we refer mainly to the trough concentrations. Therapeutically, the assumption is that if we dose according to published guidelines, we will achieve target concentrations at the site of action. In reality, we do not know that for certain. In fact, we have absolutely no idea whether we are dosing too much or too little, and basically act on faith that a certain dose (quantum and frequency) will allow trough concentrations at the site of action to exceed the MIC.
Therapeutic drug monitoring of clarithromycin had been proposed, but has never ever been taken up seriously for it to be included in routine patient management.
This is fine, if there were no serious toxicities, because you can administer more drug than really necessary just to make sure you have adequate concentrations at the target site. However, clarithromycin use does carry a serious risk of toxicity....namely sudden death. Therefore the correct dosing schedule is important to deliver only adequate levels of clarithromycin so that the troughs are over the MIC and the peaks do not approach the IC10 of IC20 of HERG channel blockade.
Currently we have no means to doing this.
On the flip side of the coin, there is the problem of cardiac toxicity. Although there is a considerable gap between routinely achieved levels of clarithromycin and the IC10 or IC20 of HERG channel blockade, obviously this gap can sometimes, though rarely, be crossed. The Danish study suggests this might be happening at least in 37 out of 1 million dosing regiments. How do we monitor and manage this? Routine ECG to look for QT prolongation would certainly be helpful. But this is almost never done during clarithromycin use.
Effectively therefore we have no means to manage variability where clarithromycin use is concerned. There is an over-dependence on published dosage guidelines, and faith in the adequacy and safety of these guidelines. Am I surprised by the association with cardiac deaths? Definitely not. Understanding the pharmacology of clarithromycin, this risk is predictable. The risk is not high. But one sudden death occurring in a relatively healthy individual, no matter how infrequent, is one death too many.
Can we do better? Yes.
If we just consider the anti-microbial effects.... we actually manage the variability rather badly. Theoretically, there is a therapeutic target that is based on maintaining drug concentrations at the target site (where the bugs are actually growing) above the minimum inhibitory concentrations (MIC). By drug concentrations we refer mainly to the trough concentrations. Therapeutically, the assumption is that if we dose according to published guidelines, we will achieve target concentrations at the site of action. In reality, we do not know that for certain. In fact, we have absolutely no idea whether we are dosing too much or too little, and basically act on faith that a certain dose (quantum and frequency) will allow trough concentrations at the site of action to exceed the MIC.
Therapeutic drug monitoring of clarithromycin had been proposed, but has never ever been taken up seriously for it to be included in routine patient management.
This is fine, if there were no serious toxicities, because you can administer more drug than really necessary just to make sure you have adequate concentrations at the target site. However, clarithromycin use does carry a serious risk of toxicity....namely sudden death. Therefore the correct dosing schedule is important to deliver only adequate levels of clarithromycin so that the troughs are over the MIC and the peaks do not approach the IC10 of IC20 of HERG channel blockade.
Currently we have no means to doing this.
On the flip side of the coin, there is the problem of cardiac toxicity. Although there is a considerable gap between routinely achieved levels of clarithromycin and the IC10 or IC20 of HERG channel blockade, obviously this gap can sometimes, though rarely, be crossed. The Danish study suggests this might be happening at least in 37 out of 1 million dosing regiments. How do we monitor and manage this? Routine ECG to look for QT prolongation would certainly be helpful. But this is almost never done during clarithromycin use.
Effectively therefore we have no means to manage variability where clarithromycin use is concerned. There is an over-dependence on published dosage guidelines, and faith in the adequacy and safety of these guidelines. Am I surprised by the association with cardiac deaths? Definitely not. Understanding the pharmacology of clarithromycin, this risk is predictable. The risk is not high. But one sudden death occurring in a relatively healthy individual, no matter how infrequent, is one death too many.
Can we do better? Yes.
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