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Example: how to avoid overestimating and underestimating a patient’s renal function

Example: how to avoid overestimating and underestimating a patient's renal function
The dosing regimen of a drug might need to be adjusted if F A is a false statement. The drug has a low fe. The drug would need to have an fe greater than 0.3 generally for us to be concerned about it. Cause fe is the urinary excretion unchanged of the drug. B is a true statement. The dosing regimen of a drug might need to be adjusted if the patient has a low GFR. And when we said GFR generally lower than sixty is a concern. C is a false statement. The dosing regimen of drug might need to be adjusted if the patient has a low serum creatinine.
It would be a high serum creatinine that would cause us to suspect that the patient might need to have a dosage adjustment. So the answer to this question is B.
Let me provide an example of creatinine clearance dosing. We have a patient who’s a 50 year old female, weighs 95 kilograms, it’s 5 foot 10, which produces an ideal body weight of 68.5 kilograms. There’s a serum creatinine of 1.6 milligrams per deciliter. If we calculate creatinine clearance using the Cockcroft-Gault equation. Using both actual body weight and ideal body weight, we discover that the patient has a creatinine clearance of 63 milliliters per minute using actual body weight, at 45.5 milliliters per minute using ideal body weight. Now, if we were to use that 40 percent fudge factor to identify an adjusted body weight, the creatinine clearance would be 52.5 milliliters per minute using that adjusted body weight.
Relating this to the dosing guidelines for Sitagliptin, we see that the standard dose is 100 milligrams per day. However, the guidelines indicate that if the patient has moderate renal failure, as indicated by a creatinine clearance of about 30 to 50 milliliters per minute, the dose should be 50 milligrams once a day. They have severe renal failure, end-stage renal disease, such that the creatinine clearance is less than 30 milliliters per minute. The dose should be 25 milligrams once a day. Now, a couple things to point out here. First of all, the dosing guidelines are no liters per minute not milliliters per minute per 1.73 meters squared.
So, we have a clue that these guidelines are probably based on estimates using the Cockcroft-Gault equation. Because if the guidelines were based on MDRD or CKD-EPI, the values would most likely be represented in milliliters per minute per 1.73 meters square. But what’s critical here is that we’ve got to be consistent in the units that we’re comparing. We’ve used the Cockcroft-Gault equation which produces values of milliliters per minute, and guidelines are based on creatinine clearance measured in milliliters per minute. So we have a consistency here. The other consideration is the fact that we have an obese patient, and we can’t really trust the Cockcroft-Gault equation result using actual body weight, because that’s probably an overestimate.
The value using ideal body weight is probably an underestimate. And we can’t be certain that the adjusted body weight is perfect for this patient This is a good indication of where there are some options, and clinicians have to use their clinical judgment as to how to make a decision in this type of a situation. If we use the adjusted body weight, and suggest that the creatinine clearance is 52.5 milliliters per minute, that would indicate that since it’s above 50, we should give the patient 100 milligrams daily. However, when we consider the fact that the ideal body weight measurement of the Cockcroft-Gault equation provided a credit clearance of 45.5 milliliters per minute, which is a little bit under 50.
And there are some institutions that recommend routinely using ideal body weight for obese patients with the Cockcroft-Gault equation So there’s some decision-making here to be made. One of the things that we’ve recommended and this was an article published back a couple years ago in Annals of pharmacotherapy, is to use rather than a specific value for patients creatinine clearance, when an obese patient is having the Cockcroft-Gault equation used to estimate creatinine clearance, is to actually use the range produced using actual body weight and ideal body weight. In this case, we would say the patient’s creatinine clearance is very probably between 45.5 and 63 milliliters per minute. It’s probably not exactly equal to 52.5 milliliters per minute.
So why not use the range as a comparison to the dosing guidelines. And when we do that, we see that there’s a possibility that the patient may need a dose of 100 mg a day because the serum, excuse me, the creatinine clearance is above 50, but it quite possibly could be a little bit below 50. And it leads it to the judgment of the clinician. Do you want to be more aggressive, or more conservative? But using a range of creatinine clearance for an obese patient with Cockcroft-Gault gives you the options, and it provides a very strong probability that the patient’s creatinine clearance is somewhere within that range.
There are differences between hepatic and renal drug elimination, and these have to be considered in drug dosing. Filtration versus metabolism is an important consideration. Renal filtration is a passive removal process like a swimming pool filter. And hepatic metabolism is an active messy enzymatic biotransformation process. Estimating kidney or liver function is also very different. With renal function, we can accurately estimate or quantify a patient’s GFR or creatinine clearance. When it comes to estimating liver function, it’s a very different process. The best we can do is come up with a basic qualitative assessment that may or may not relate directly to whether or not there’s a need to adjust the patient’s drug dosing.
There are three parameters that are frequently used as indicators of whether a patient has impaired hepatic function. One is a decreased albumin level because albumin is produced by the liver. Also an increased INR because the liver produces clotting factors. And an increased bilirubin because the liver breaks down bilirubin. So, any of those could be used as indicators that the patient’s renal, excuse me, hepatic function might be impaired. We often use liver enzymes, an elevation of liver enzymes as an indicator of hepatic status. But keep in mind that liver enzymes are not specific measures of liver function. They simply indicate whether or not there has been some hepatocytes damage, this allowed those enzymes to leak out into the serum.

After a brain exercise for the timing to adjust the dose, Prof. Brown gives an example for Januvia (Sitagliptin) adjustment.

When the value of CLcr using ideal body weight (IBW) is an underestimate, and the value of CLcr using actual body weight is an underestimate, what will you do?

Do you want to be more aggressive, or more conservative on the drug use? It is not easy to make the decision, however, you can find some clues in this video.

Finally, he clarifies the differences between hepatic and renal drug elimination. What are the differences between estimating liver and kidney function? Please leave your answer below and explain why.


Prof. Daniel L. Brown

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Clinical Pharmacokinetics: Dosing and Monitoring

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