Dose Adjustment in Renal Disease

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 prolongs its half life (t? ) as well as the time required for the serum level to reach a steady state (4 times t? ). Therefore, whenever it is clinically desirable to rapidly achieve a therapeutic steady state level a loading dose should administered. To maintain a therapeutic level and, at the same time, avoid drug accumulation and toxicity in a patient with reduced renal function, the clinician must consider reducing the size of the maintenance dose or the dosing frequency or both. In general, this reduction should also be proportional to the degree of renal impairment , but should also take into account adaptive or compensatory changes in the metabolism and excretion of the drug through non-renal routes. MAINTENANCE DOSE REDUCTION METHOD: The maintenance dose reduction method is used whenever a more constant (less oscillating) serum drug level is therapeutically preferable (e. . , ? -lactam antibiotics) Let us assume that one has already defined a safe and effective dose regimen for use in normal patients. This normal dose regimen is then adjusted according to dose fraction by two basic procedures. First method termed as constant interval, dose-reduction (DR) reduces the dose (D) by a factor of the dose fraction. Dose interval is the same as that used in the health person. D renal failure = D normal Kf t renal failure = t normal INTERVAL EXTENSION METHOD The second method referred to as constant dose, interval-extension(IE) extends dose interval by inverse of dose fraction, a value referred to as the dose interval multiplier : t renal failure = t normal (1/ kf) D renal failure = D normal This type of dose adjustment strategy may also be implemented through the use of a nomogram where the dosage interval multiplier for this IE regimen is simply read off a plot of creatinine clearance Interval extension method is used for drugs for which a constant serum level is either unnecessary (eg, vigabatrin) or undesirable (e. g. , aminoglycoside antibiotics). This method is also used for drugs that normally have long elimination t?. However, a combination of the two methods is often used. In addition, for a drug whose therapeutic serum level range is known and routinely measured, dosage adjustment is often guided by monitoring the serum drug level and the patient's response in terms of the therapeutic benefit and adverse drug reactions (toxic ity). Reference:: http://www. hedrugmonitor. com/RIT97. html http://books. google. com. pk/books? id=qXw33GaQF9IC=PA288=PA288=general+approaches+to+dose+adjustment+in+renal+patients=bl=IKsqNAp2nU=jglKfgGimUFQ_xBN9cGKPPRsC2E=en=CxbTStLaAo-QkQX1_N30Aw=X=book_result=result=7=0CCMQ6AEwBjgK#v=onepage=general%20approaches%20to%20dose%20adjustment%20in%20renal%20patients=false http://www. gbv. de/du/services/toc/bs/380847361 http://books. google. com. pk/books? id=9324ILATCgMC=PA288=general+approaches+to+dose+adjustment+in+renal+DISEASE#v=onepage=general%20approaches%20to%20dose%20adjustment%20in%20renal%20DISEASE=false