GENERAL APPROACHES FOR DOSE ADJUSTMENT IN RENAL DISEASE
Renal insufficiency can markedly alter one or more of the pharmacokinetic parameters of a drug including oral bioavailability, volume of distribution, drug binding to plasma proteins, and most importantly the rates of metabolism and excretion, i.e., drug clearance.. To minimize drug toxicity and maximize therapeutic benefits, it is often necessary to adjust drug dosage in proportion to the degree of renal insufficiency. A drug will most likely require dose adjustment in renal disease if: 1. A substantial fraction (> 40%) of the drug dose is excreted by the kidney either unchanged or as an active (or toxic) metabolites. 2. The drug or its active metabolite has a narrow therapeutic window such that drug accumulation cannot be tolerated. 3. The kidney is a major site for the inactivation of the drug. This applies mainly to peptides like insulin, glucagon, PTH, and imipenem. 4. There is a significant drop in the binding of the drug to plasma proteins. For instance, a decrease in the protein binding from 99 to 95% results in a fourfold rise in the unbound, active drug concentration. Dose adjustment may involve one or a combination of the following measures: 1. Extension of the dosing interval.
2. Reduction of the maintenance dose.
3. Administration of a loading dose.
4. Monitoring serum drug levels.
FACTORS IN CHOOSING OF DOSE ADJUSTMENT APPROACH:
Factors to consider when choosing appropriate dose adjustment approach are the class of drug ,the amplitude of the peak-trough fluctuation relative to the therapeutic index, magnitude of the dose with respect to the dose strength to be marketed and practicality of calculated dosing interval. Pharmacokinetic simulations can be especially helpful in visualizing the impact of various dose and interval changes and interval changes on the concentration time (C-T) profile at steady state. Reduced elimination of a drug...
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