Guidelines for CLINICAL DRUG USE ~ F.A.Q. ~
D. CRAIG BRATER, M.D. Dean, Indiana University School of Medicine Professor of Medicine and Pharmacology Indianapolis, Indiana	Copyright Improved Therapeutics, Inc. Indianapolis, Indiana 1992
PREFACE The first two editions of this work focused on drugs eliminated by the kidney and offered dosing recommendations for patients with diminished renal function. This approach continues to dominate, but in subsequent editions, I have attempted to broaden the scope to include all drugs used clinically and in addition to include data on the effects of other diseases on disposition of drugs. Where data exist, dosing recommendations are now offered for a variety of clinical conditions, which include hepatic and cardiac disease, and conditions affecting the elderly. The same admonitions apply to this edition as applied to the first; namely, guidelines such as these serve only as a starting point for therapy and from which dosing must be tailored to the needs of the individual patient. Variability among patients in disposition of drugs is so great that one must assume that all patients will need additional "fine tuning" of their dosage regimen. D. Craig Brater GUIDELINES This handbook focuses on drugs for which a disease process or aging affects kinetics or dynamics of response in a clinically significant way. The drugs are arranged alphabetically by class with specific kinetic data and guidelines for dosing. If a drug does not appear, it either has not been marketed for general use, was not deemed close enough to market to warrant consideration, or has been inadvertently overlooked. The data are a synthesis of results from studies felt to be most accurate for each drug. In some instances, parameters have been recalculated. The data are derived from studies in adults and should be extrapolated to infants and children with caution, if at all. USE OF GUIDELINES For the most part, data on specific drugs include the percent excreted unchanged in the urine, whether or not active metabolites are formed and whether these metabolites accumulate in disease, extent of protein binding, volume of distribution, parameters of elimination, including dialyzability, and specific comments including dosing guidelines that are related to disease and its severity. Excreted Unchanged In general, the degree to which accumulation of a drug may occur in uremia is directly related to the percent excreted unchanged in the urine. Unless about 40 percent or more of a parent drug or its active metabolite is eliminated by the kidney, renal dysfunction is unlikely to mandate dose adjustment. Active Metabolites It is important to emphasize that one must be concerned with the disposition of potentially active metabolites in addition to the handling of the parent drug. Protein binding The degree of a drug's protein binding can lead to certain predictions about its handling and possible changes with renal and hepatic dysfunction. Drugs, usually acidic, that are bound to albumin in excess of 90 percent are subject to displacement by other tightly bound drugs or by accumulated endogenous products in uremia. In addition, protein binding decreases as albumin levels decline with age or disease. The increased unbound drug in either scenario is then available to the distribution space or to pathways of elimination. The net effect of these factors is an increased volume of distribution (based on concentrations of total drug) and a lower serum concentration of total drug in the face of a concentration of free drug the same as occurs in normal subjects. The unchanged concentration of free drug means that pharmacologic effect is the same. The clinical importance of this effect is that the "therapeutic range," expressed in terms of total drug concentration, may decrease; therefore, a low total concentration should not necessarily be misinterpreted as subtherapeutic. The degree of protein binding may also influence dialyzability. Drugs tightly bound to proteins are unable to cross dialysis membranes. However, these same drugs might still be extracted from blood by resin hemoperfusion. Volume of Distribution Volume of distribution is expressed in L/kg. Data In these tables that are gleaned from studies in adults but have been reported solely as volume not factored for body weight have been assumed to represent those of a 70 kg subject. The volume of distribution in the ensuing data represents Vd beta or Vd area and is the total volume into which drug distributes in the body; therefore, clearance equals the product of Vd and the elimination rate constant. Drugs with a large volume of distribution have a large clearance, and as a consequence, hemodialysis is less likely to contribute to overall elimination in a significant manner. A change in the volume of distribution caused by a disease process or by aging may mandate a compensatory change in the loading dose of a drug. It does not affect the maintenance dose. Clearance Elimination is expressed in terms of clearance and half life. Clearance (Cl) is presented as ml/min/kg. As with volume of distribution, some of the data were derived presuming studies in adults to represent 70 kg of body weight. In patients with renal disease, values for elimination parameters or a qualitative statement are presented; end stage renal disease (ESRD) represents ClCr less than 20, moderate represents ClCr greater than 20 and less than 50, and mild represents ClCr greater than 50 ml/min/1.73 m2. In the regressions, entering ClCr corrected in terms of body weight computes the clearance as ml/min/kg. From the regressions, one may calculate a half-life at a specific level of renal function: Dialysis The reader may wish to use specific calculations of pharmacokinetic parameters to derive dosage modification for an individual patient. Dialyzability is expressed in terms of half life and the percent of a dose removed by the dialytic procedure. It is important to emphasize that for dialysis to be considered important for dose adjustment or as a therapeutic maneuver, it must contribute to overall clearance in a clinically meaningful amount, usually increasing clearance at least 30 percent over that without dialysis. In the dialysis comments, specific mention may not be made about drug removal by hemofiltration. The increment in dosing needed in this setting can be calculated assuming that the only drug available for removal is that which is unbound. Dosing Guidelines Specific comments are directed toward dosing guidelines, which, for the most part, are expressed as a fraction of the "normal dose" rather than as specific recommendations on a mg/kg. This approach was deemed most useful, because the "normal dose" in a patient may differ depending on the treatment strategy. With many drugs, I have arbitrarily elected to suggest guidelines for the following categories of renal function: ClCr greater than 50, ClCr less than 50 but greater than 20, ClCr less than 20, and dialysis. With each category, a range is suggested as a fraction of the normal dose, the smallest fraction applying to the lowest renal function in that category and the largest fraction to the highest level of renal function. To obtain intermediate levels of renal function, the clinician should interpolate within the suggested range. For drugs that have a narrow therapeutic index, more precise guidelines are offered. The user must remember that these recommendations are based on data derived from populations of patients and extrapolated to the individual. Inter individual variability is great, and as a consequence, these guidelines do not achieve the predicted drug concentration in all patients -in fact, only for the idealized "average" patient. The guidelines are best used as a starting point with more precise dose adjustment based on determinations of serum concentrations and evaluation of clinical end points in the individual patient.