How to assess the need to change drug dosing ?

Welcome back to clinical applications of pharmacokinetic dosing and monitoring.

This is section four : Challenges of assessing renal and hepatic clearance. The question that we’ll try to answer in this video is how can we accurately assess the need to change drug dosing based on renal or hepatic function. After this lesson, you should be able to describe methods used to estimate creatinine clearance and glomerular filtration rate or GFR. Should be able to identify sources of error of the Cockcroft-Gault equation. Should be able to explain the purpose and process of correcting creatinine clearance to 70 kg or 1.73 meters squared. Should be able to determine F, the bioavailability or E, the extraction, given FG or FH, the bioavailability in the gut and the bioavailability of hepatic extraction.

For both high E and low E drugs, determine how the three factors of hepatic extraction fraction unbound, liver blood flow and intrinsic clearance affect the unbound concentration and the total concentration of drug, and also the bioavailability. Describe the relationship between Vmax, Km and intrinsic clearance. And explain the clinical implications of dosing a “Michaelis-Menten” drug. Let’s begin by considering some of the terminology that relates to the disappearance of drug. From the blood, how to describe processes that cause drugs to disappear from serum? First of all, we spent a lot of time talking about clearance clearance, refers to the volume of blood that has drug removed from it per unit time.

Elimination is a general term that describes the disappearance of drug from the serum by virtue of the fact that we notice a decrease in serum concentration. So when we say a drug is being eliminated from the serum, we simply mean that the serum concentration is declining. Excretion is a more specific process. It defines the actual elimination of drug from the body. Such as urinary excretion with the drug being removed by the kidneys and excreted in the urine. Filtration is a particular type of excretion that refers to the kidneys with the drug being filtered out of the blood by the kidney Metabolism is a different process entirely.

It refers to the liver metabolism of drug, which implies the following term biotransformation, whereas filtration excretes the drug from the blood and from the body. Metabolism changes the drug, changes the form of the drug, such that in many cases it’s no longer active. And this is a biotransformation process. You’re not actually removing the drug molecule but changing it so it’s no longer the same molecule. And lastly extraction, which refers to the hepatic elimination. This extraction refers to drug that enters the liver, and disappears during the process of passing through the liver. So it’s said to have been extracted by the liver. Now let’s begin by exploring renal clearance.

We’ll focus on the kidneys first, and then the mechanisms of hepatic elimination. First by measuring glomerular filtration rate, GFR. This involves primarily a measurement of serum creatinine, which is the primary marker of renal function. in terms of a laboratory test, it’s the standard renal function monitoring parameter. Creatinine is produced by metabolizing muscle tissue, but it’s eliminated by the kidneys. Creatinine clearance relates very closely to glomerular filtration rate. Creatinine clearance can be determined directly by a urine volume collection method, or estimated using a relationship between the serum creatinine and creatinine clearance.

When we use the urine collection method, we actually collect the amount of urine that’s excreted excuse me, we collect the urine that contains the excreted creatinine, and by the amount of creatinine that’s been excreted, and comparing that amount to the creatinine concentration in the serum can identify the actual volume of blood that had creatinine removed from it. Based on the amount that was excreted in the urine, it’s a more accurate process than the estimation of creatinine clearance. Creatinine clearance estimation methods. There are three primary methods that are used. The first one is the Cockcroft-Gault method, which we’ll be talking about in more detail. This was developed back in 1976.

The interesting thing about the Cockcroft-Gault estimation method is that it provides a creatinine clearance in milliliters per minute. Slightly different process is involved in the MDRD, the modified diet and renal disease study process This is an equation that was developed in 2000. It was modified in 2006 to account for more refined creatinine assay, more accurate creatinine assay. Now the interesting thing about MDRD in comparison to the Cockcroft-Gault estimation method is that the MDRD method provides a GFR, whereas Cockcroft-Gault estimates creatinine clearance. There is a slight difference between the two. Creatinine is both filtered by the kidneys which is a primary elimination, but it’s also secreted by the kidneys. GFR strictly measures glomerular filtration.

So we would expect the creatinine clearance to be slightly higher than the GFR, because there’s that secretion mechanism which accounts for about 10 percent of the elimination of creatinine. The other difference between MDRD and Cockcroft-Gault is that the MDRD produces a result that is already adjusted to body size, and the units for GFR and MDRD in milliliters per minute per 1.73 meters squared or as Cockcroft-Gault, the units are simply milliliters per minute because the value is not corrected to body size.

And the third type of creatinine estimation method is the chronic kidney disease epidemiology collaboration equation, the CKD-EPI, which was developed in 2009, and then it was modified in 2012 to include not only the measurement of serum creatinine but cysteine C as well. It also produces a result in GFR that is corrected to milliliters per minute per 1.37 meters squared. History of the Cockcroft-Gault equation is very interesting. We’ll take a look at that first, and then discuss the MDRD and a CKD-EPI equations. The original study was published back in 1976. It’s the most widely referenced article in the medical literature, in the history of medical literature. So it’s a very popular study and a very widely used equation.

The study that produced the Cockcroft-Gault equation was conducted in Veterans Hospitals in Canada. It studied the creatinine clearance from urine collection an accurate measurement of creatinine clearance. Against four methods for estimating creatinine clearance from serum creatinine. And the idea here is that there’s an inverse proportion between the serum creatinine concentration and a patient’s creatinine clearance. And the idea of the Cockcroft-Gault study was to identify that relationship mathematically such that an equation could be generated that could be used for any patient to convert their serum creatinine to an estimated creatinine clearance. The study population. This is very interesting. It was mostly male Canadian veterans.

The study did not provide information on the weights of all the patients or the breakdown of weights, only provided a mean. There’s an indication that these patients were probably not obese, so the patient population may differ quite a bit from various populations in the world today. The findings showed of a mathematical linear regression when 140 minus the patients age, was multiplied by patient weight, this is actual body weight, divided by the serum creatinine concentration times 72.

Now, what they decided to do in the study there weren’t very many females in the study only 4% of the subjects were female, so they couldn’t really break it down between male and female, but just based on the fact that they estimated that female muscle mass is about 85%, that of a male they added the 0.85 factor to the equation. So this was an arbitrary decision.

The newer eGFR equations. Again, they focus on estimations of GFR rather than creatinine clearance. But they still use serum creatinine as the primary laboratory value. The MDRD equation, as shown on the slide here, uses negative exponents for the serum creatinine, the patient’s age, gender. In this case, if the patient is female. And the MDRD also uses race. It adjusts the value if the patient is African American. CKD-EPI again uses serum creatinine as the primary laboratory value, and it also uses exponential equations to adjust for age, gender, and race. If the patient is African American. Note that both the CKD-EPI and the MDRD equations do not include any function of weight.

That distinguishes them from the Cockcroft-Gault equation, for which weight produces a great deal of controversy in the clinical arena today. CKD-EPI also as a mentioned in 2012 was modified to include cysteine C It’s not known whether the addition of cysteine C improves the predictability of crediting clearance or not, but it’s one option that’s available out there.