Pharmacokinetic principles during continuous renal replacement therapy: drugs and dosage

Some drugs are removed significantly by continuous renal replacement therapies (CRRTs), and a substitutional dose is required to prevent underdosing of the substance. This review outlines the basic pharmacokinetic principles that determine whether a dose adjustment is required. Only the free non-protein-bound fraction of a drug can pass through the dialyzer membrane. In postdilution hemofiltration the drug clearance equals the ultrafiltration rate, while in predilution hemofiltration, the dilution of the blood prior to filtration needs to be considered when calculating clearance. In continuous hemodialysis, drugs are eliminated by diffusion. Drugs with a higher molecular weight will diffuse more slowly and show a lower clearance than smaller drugs. The clinical relevance of a given drug clearance caused by CRRT will mainly depend on the competing drug clearance by other elimination pathways. Even a high clearance for a drug may be irrelevant for overall drug removal if nonrenal clearance pathways provide a much higher clearance rate. The ideal drug to be removed by CRRT that requires a dose adjustment has: a low protein binding, a low volume of distribution, and a low nonrenal clearance. Examples include aminoglycosides, vancomycin, fosfomycin, and flucytosine. Even if there are no studies available on the pharmacokinetics of a particular drug during CRRT, knowledge of the basic concepts of drug elimination by continuous hemodialysis allows a prediction of whether or not a dose adjustment will be required during CRRT.