Based on the well known linear relationship between the overall drug elimination rate constant and the endogenous creatinine clearance, it is shown how individual drug elimination parameters in patients with renal disease can be estimated from the patient's creatinine clearance or serum creatinine concentration. By means of a simple nomogram the elimination rate fraction is determined which describes the elimination rate of the drug as a fraction of its normal elimination rate constant. Based on the estimated elimination rate fraction the dosage regimen in the patient with renal disease is individually modified according to pharmacokinetic principles. At present the described method can be used with 45 different drugs.
The concentration-time profile of ethanol in breath air (AAC), arterial (ABAC) and venous blood (VBAC) of human volunteers was studied after four different oral doses of absolute alcohol--0.5, 0.75, 1.0, and 1.25 g/kg body weight. Seventy-eight single dose experiments were carried out in 42 subjects. In all 78 studies AAC was measured and VBAC was estimated simultaneously in blood collected from a cubital vein of 36 volunteers. Arterial blood, too, was collected from 8 subjects from a catheter in a brachial artery. All blood alcohol concentrations were analysed independently by gas chromatography (GLC) and an enzymatic (ADH) method. A one-compartment open model with first order absorption and pseudo-zero-order elimination was employed to calculate the pharmacokinetic parameters. The average values for the first order absorption rate constant (ka) ranged from 2.2 to 3.1, from 2.4 to 2.6 and from 1.0 to 1.7 h-1 for ACC, ABAC and VBAC, respectively. The pseudo-zero-order elimination rate constant (beta) was 0.17 to 0.18, 0.21 to 0.22 and 0.26 to 0.27 g X 1(-1) X h-1, respectively. During absorption ABAC tended to be higher than VBAC, peaking at a higher level (Cmax) and with a shorter time to peak (tmax) until an arterio-venous concentration equilibrium was reached, whereafter VBAC remained above ABAC. Although there was a close relationship between AAC, ABAC and VBAC during elimination, AAC closely followed the pattern of ABAC during absorption and tended to deviate from VBAC. AAC, therefore, is a much better predictor of ABAC during absorption than VBAC.
Patients with renal impairment excrete drugs more slowly than normal individuals. Ta avoid the increased risk of toxicity as the consequence of drug accumulation tollowing repeated administration of the “usual” dose, the dosage regimen has to be modified in aceordanee with the lower speed of drug elimination. A simple graphie method is deseribed to estimate the individual overall elimination rate constant of a drug trom the ereatinine clearanee of the patient with renal disease. Based on the estimated elimination rate eonstant, the individual dosage regimen is ealculated according to pharmaeokinetie principles. As a result, two simple dosage rules tor intermittent and for eontinuous administration of drugs to patients with renal impairment are reeommended. For special circumstanees, two more sophistieated dosage rules are given.
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