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Skip to 0 minutes and 11 seconds In dealing with dosing adjustment in renal failure. We need to be cognizant of the assumptions. First, the assumptions related to the patient. We assume that renal failure patient and the otherwise normal patient share the same therapeutic concentration, nonrenal clearance, volume distribution, absorption and receptor sensitivity. Assumptions related to the drug itself. Now for renal failure patient, and otherwise normal patient The drug follows the same kinetic order. Or the drugs clearance is proportional to the creatinine clearance. And that the drug has the same tissue uptake. The assumptions or this assumptions are generally valid.

Skip to 1 minute and 14 seconds However, there are exceptions Therefore, a rational approach is to initiate the dosing regimen based on these absorptions followed by therapeutic drug monitoring and the so called “learn and adapt”. That during the learn and adapt process it may involve corrections for these assumptions. Now to keep the assumptions at the minimum, use patient specific PK information if available. Now, let’s look at the dosing regimen equation. Dosing regimen equations are derived based on IV infusion, or oral administration. Let’s start with constant rate intravenous infusion. Now if we infused a drug at constant rate for greater than 5 half-lives. Then the drug would reach at steady state. At the steady state, the concentration is equal to the infusion rate over the clearance.

Skip to 2 minutes and 33 seconds Now if we assume same therapeutic concentration then, the equation is transformed into the second one which indicate that the infusion rate in uremic patient is equal to the uremic infusion rate in normal patient times the clearance ratio. Therefore, the correction factor is the clearance ratio. Again, here C is the steady-state concentration which is defined generally as the therapeutic concentration.

Skip to 3 minutes and 19 seconds R: is the infusion rate.

Skip to 3 minutes and 22 seconds Cl: is the total clearance.

Skip to 3 minutes and 24 seconds and N: denotes normal kidney function.

Skip to 3 minutes and 28 seconds U: denotes uremic. Now if derived to base on oral administration. By the same token if a drug is given orally on a chronic basis or on multiple dose basis then eventually the drug will reach at steady state concentration. At steady state, the rate of drug input is equal to the rate of drug output. Rate of drug input is a fraction of the dose divided by Tau dosing interval. The rate of output is clearance times steady state concentration. Sorry, I need to back up a little bit and that therefore the steady-state concentration or the average steady-state concentration is equal to F dose over clearance times Tau. Here again just quickly the definition or the denotation. F is bio-availability.

Skip to 4 minutes and 28 seconds D is a dose. Tau is the dosing interval. Cl is the total clearance. and the Css is the average steady-state concentration.

Dosing Adjustment: Assumptions and Dosing Regimen

In this step, Prof. Lee explains how to adjust the dosing regimen in renal failure.

If the IV infusion rate is constant, we can assume the same therapeutic concentration (Css), and use the relationship between infusion rate (R) and total clearance (Cl) to get what we want.

If the drug is administrated orally, we should consider the bioavailability (F), and use the final formula in this step to calculate its dosing regimen.

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This video is from the free online course:

Pharmacokinetics: Drug Dosing in Renal Disease

Taipei Medical University