CLcr Values Research Articles

Urea kinetics and dialysis treatment time predict vancomycin elimination during high-flux hemodialysis.

Hemodialysis sessions with high-flux filters ask for a reconsideration of the kinetics of xenobiotics. The aim of this study was to analyze whether individual high-flux hemodialysis treatment parameters are of predictive value for dosing guidelines, with use of vancomycin as a model compound. Twenty-six patients receiving high-flux hemodialysis were studied prospectively. After an intravenous infusion of 1000 mg or 500 mg vancomycin, respectively, six to eight blood samples were collected within a period of 5 to 9 days, including one hemodialysis session. Serum vancomycin concentrations were measured by HPLC. Nonlinear mixed-effects modeling (NONMEM) was used to fit a two-compartment population pharmacokinetic model to the data of 20 patients; the data of the remaining six patients (group II) were used for a prospective evaluation of the model. A linear relationship was found between vancomycin filter clearance (CLDV) and urea filter clearance (CLDBUN), derived from Kt/V (the product of urea clearance [K] and dialysis treatment time [t], standardized for the urea volume of distribution [V]). Mean (coefficient of variation) steady-state volume of distribution was 1.05 L/kg (22%), CLDV was 0.336.CLDBUN (13%), and residual interdialytic clearance was 2.25 ml/min (90%) in patients with creatinine clearance values (CLCR) below 2 ml/min and 2.25 ml/min + 0.59.CLCR (32%) in patients with CLCR values above 2 ml/min. The model predicted predialysis vancomycin concentrations before the first and the second postinfusion dialysis session in the six patients of group II, with a deviation of 1.8 +/- 1.0 mg/L and 0.8 +/- 0.5 mg/L, respectively. The described population pharmacokinetic model allows individualization of vancomycin dosing intervals in patients receiving hemodialysis, based on patient characteristics and urea kinetic modeling.

血中濃度からみたジゴキシンの用量設定に関する現状分析と，患者腎機能に対応した用量設定に向けての簡便な指標の構築

To elucidate the current status of the dosage regimen of digoxin (DX), we reviewed its therapeutic drug monitoring (TDM) data obtained from 50 patients on whom TDM was performed for the first time following the beginning of DX treatment. The serum trough level of DX in 50% the subjects deviated from its therapeutic range (0.5-1.5 ng/ml) because the uniform dosage (0.125-0.148 mg/day) was administered for the patients with various degrees of renal functicns. The serum levels of DX in about 70% of the patients with normal renal function (80 ml/min≤ creatinine clearance. CLcr) were less than its lower limit (0.5 ng/ml), and those in about 70% of patients with severe abnormal renal function (CLcr<40 ml/min) exceeded its upper limit (1.5 ng /ml).To design a simple index for the dosage regimen of DX whith closely corresponded to the renal functions in patients, 286 samples of TDM data obtained from 87 patients who were not coadministered drugs known to alter DX pharmacokinetics were reviewed by dividing then into three groups according to the CLcr values. The mean serum DX levels (0.7-1.2 ng/ml) in each group could be kept at their therapeutic range, as the dosages were respectively 0.25 mg/day (80 ≤CLcr group), 0.125-0.25 mg/day (40≤CLcr<80 group), or 0.0625-0.125 mg/day (CLcr< 40 group).These results indicate that the minimum dosages of DX in each reual function group, which were expected to maintain its effective serum level (0.7 ng/ml) within the lower limit of the therapeutic range, are desirable from a safety, that is, the optimal dosages of DX as an indication in the early dosing stage are respectively 0.25 mg/day for patients with normal renal function (80≤CLcr), 0.125 mg/day for patients with moderate abnormal renal function (40≤CLcr< 80), and 0.0625 mg/day for patients with severe abnormal renal functicn (CLcr<40).

Lansoprazole pharmacokinetics in subjects with various degrees of kidney function.

The pharmacokinetics of lansoprazole, a new benzimidazole proton pump inhibitor, was evaluated after multiple-dose oral administration to 20 subjects with various degrees of kidney function. Multiple blood samples were obtained after doses 1 and 7 of the once-daily seven-dose regimen, and plasma concentrations of lansoprazole and five metabolites were quantitated with use of HPLC. The free fraction of lansoprazole increased as kidney function declined. A significant, although weak, relationship existed between creatinine clearance (CLCR) and area under the plasma concentration versus time curve (AUC) and terminal disposition half-life (t1/2), calculated with total concentration data. Those individuals with lower CLCR values also had lower total AUC and t1/2 values. However, there was no statistically significant relationship between CLCR and peak plasma concentration or AUC, calculated with unbound concentration data. No adjustment of lansoprazole dose is recommended on the basis of impaired kidney function.

Creatinine-clearance estimates for predicting gentamicin pharmacokinetic values in obese patients

The Cockcroft-Gault and Salazar-Corcoran equations were compared with respect to prediction of gentamicin pharmacokinetic values in obese and nonobese patients, and the results were used to formulate guidelines for calculating initial gentamicin dosages in obese patients. Creatinine clearance (CLcr) was estimated by applying the Cockcroft-Gault equation using total body weight (TBW), ideal body weight (IBW), and dosage weight (DW) and with Salazar-Corcoran equations using fat-free body mass (FBM) in 100 obese and 100 nonobese patients. Gentamicin pharmacokinetic values (k, CL, and t1/2) were estimated by using CLcr estimated by each method and standardized to a body surface area of 1.73 sq m. Actual pharmacokinetic values were determined by using steady-state gentamicin concentrations and a modified Sawchuk-Zaske equation; these values were compared with the predicted values. In the obese patients, pharmacokinetic values predicted from standardized CLcr by the Cockcroft-Gault equation using estimated DW were not significantly biased, compared with actual values; most predictions produced by the other methods were significantly biased. Predictions produced by the DW method were generally more precise than those resulting from the other methods. In nonobese patients, k values estimated by the Cockcroft-Gault equation using IBW were not significantly biased, while values obtained with all other methods were biased. All methods were biased when predicting CL and t1/2 in nonobese patients. Significant correlations existed between standardized estimates of CLcr (by all methods) and pharmacokinetic values in both groups. Predictions of gentamicin k, CL, and t1/2 were best overall when CLcr was estimated by the Cockcroft-Gault equation using DW, rather than by other methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of Temocapril and Enalapril in Patients with Various Degrees of Renal Insufficiency

Temocapril is a novel ACE inhibitor that is cleared via dual excretion routes in humans. Borderline or mildly hypertensive patients with normal renal function [group 1, creatinine clearance (CLCR) > 70 ml/min (4.2 L/h), n = 12], moderate renal impairment [group 2, CLCR 30 to 70 ml/min (1.8 to 4.2 L/h), n = 12] or severe renal impairment [group 3, CLCR < 30 ml/min (1.8 L/h), n = 12] received a single oral dose of either temocapril 1 mg (n = 6, each group) or enalapril 5mg (n = 6, each group). These 2 drugs gave similar values for the area under the plasma concentration-time curve (AUC) of the active diacids. The maximum plasma concentration of enalapril diacid was increased 2- and 6-fold in moderate and severe renal impairment, respectively, whereas that of temocapril diacid was not altered. The AUC of enalapril diacid increased 13-fold at CLCR values < 30 ml/min, but that of temocapril diacid increased only 2-fold. The duration of plasma ACE inhibition due to enalapril was greatly prolonged by the impairment of renal function, whereas that due to temocapril was affected very little. Urinary recovery of temocapril diacid was decreased markedly in patients with severe renal dysfunction, most probably because the diacid was excreted through the biliary route. On the other hand, urinary recovery of enalapril diacid remained fairly high even in patients with severe renal impairment, because of extremely high plasma diacid concentrations resulting from the lack of biliary excretion. These observations suggest that temocapril is beneficial in the treatment of hypertension in patients with severely impaired renal function.

Validity of creatinine clearance estimates in the assessment of renal function

In clinical practice, estimations of renal function are commonly used to calculate the appropriate dose for drugs that are renally cleared. Continuous-infusion inulin clearance (CLIN), 4-hour creatinine clearance (CLCR,m), and 24-hour creatinine clearance (CLCR,a) were measured in 109 subjects (86 men and 23 women) with varying degrees of stable renal function (CLIN, 6 to 209 ml/min) and compared with CLCR values as predicted by five equations on the basis of plasma creatinine concentrations, age, weight, and/or height. The CLCR,m was positively correlated with CLIN (r = 0.92; p less than 0.0001) but exceeded CLIN by 15% between the range of 30 and 209 ml/min (CLIN). Similarly, CLCR,a correlated well with both CLCR,m (r = 0.84; p less than 0.0005) and CLIN (r = 0.84; p less than 0.0001). The relative role of tubular secretion in the overall clearance of creatinine increased with declining CLIN and exceeded 40% when CLIN was below 30 ml/min. CLCR estimated by the Cockcroft-Gault and Mawer methods did not significantly differ from either CLCR,m or CLCR,m, whereas the other equations generally underestimated CLCR. Among the numerous mathematical equations, CLCR as estimated by the method proposed either by Mawer or Cockcroft and Gault was the best predictor of CLIN (CLIN = 1.05CLRCR - 18.38 or CLIN = 1.12CLCR - 20.60, respectively; r = 0.81; p less than 0.0001). The present data support the use of estimator equations proposed by Cockcroft and Gault or Mawer for rapid estimation of renal function in the clinical setting.

Superiority of disease-specific over conventional formula in predicting creatinine clearance from serum creatinine in patients with liver cirrhosis.

To determine if liver cirrhosis may influence the accuracy of formulas estimating creatinine clearance (Clcr) from serum creatinine, we compared the measured and estimated Clcr in 95 male (group A) and 47 female cirrhotic patients (group B). The Clcr values of group A and B patients were estimated with the equations obtained from 93 male (group C) and 86 female patients (group D) who were free of liver disease: the mean estimation errors (+/- SD) for the group C and D patients with the equations obtained from their own population data were 5 +/- 24% and 4 +/- 22%, respectively. However, these equations significantly (p less than 0.01) overestimated the Clcr of cirrhotic patients: the mean estimation errors for the group A and B patients were 35 +/- 43% and 14 +/- 27%, respectively. In contrast, the mean estimation errors for the group A and B patients using cirrhotic patient-specific equations obtained from their own population data were 5 +/- 33% and 3 +/- 25%, respectively. The accuracy of these disease-specific formulas was also confirmed in a prospective manner in 43 male (group E) and 21 female cirrhotic patients (group F): the mean estimation errors for the group E and F patients were 2 +/- 32% and -7 +/- 29%, respectively. We conclude that the Clcr values of cirrhotic patients, particularly male patients, may not be accurately estimated with equations of formulas deriving from liver disease-free patients, but should be estimated using their own population data.

Nizatidine, and H2-receptor antagonist: disposition and safety in the elderly.

Nizatidine is an orally active H2-receptor blocker. Its disposition and safety in eight young and 12 elderly volunteers were investigated. Single oral doses of nizatidine were administered: from 100 mg to 300 mg in the elderly, and from 100 mg to 350 mg in the young. The nizatidine AUC was directly proportional to dose for both groups. Calculated pharmacokinetic variables in the elderly vs. the young were t1/2 = 1.9 vs. 1.6 hr; CLp/f = 32 vs. 40 L/hr, and Vd beta/f = 1.2 vs. 1.3 L/kg. The impaired renal function of some elderly volunteers prolonged nizatidine elimination and lowered its clearance. Renal impairment rather than advanced age per se was the predominant factor in decreasing the nizatidine elimination rate. Because Clcr correlated directly with nizatidine renal clearance, Clcr values may be used to estimate nizatidine dosage reductions in renal insufficiency. During the trial, no serious adverse effects occurred.

Creatinine clearance predictions in acutely ill patients

In acutely ill patients, predicted creatinine clearance (Clcr) values [obtained using the Siersbaek-Nielsen nomogram (SNN) and ideal body weight (IBW)] were compared with actual Clcr based on measured urine creatinine concentrations. Timed urine collections were obtained from 118 patients (423 collections from 68 men, 400 collections from 50 women) before, during, and after aminoglycoside therapy. Patients were in intensive care units for management of acute exacerbations of sepsis, pneumonia, or abscess; most had other complicating conditions and were chronically ill. Urine was collected for 8 to 24 hours (70% for 24 hours) from Foley-catheterized patients. Patients were divided into low (less than 15 mg/kg/day), normal (15-25 mg/kg/day), and elevated (greater than 25 mg/kg/day) urinary creatinine excretion groups. Actual body weight (ABW) was used in some patient subgroups to explore differences between using IBW and ABW. SNN most accurately predicted Clcr in the 20% of the urine collections characterized by normal urinary creatinine excretion (Ucr). Most study patients excreted significantly less creatinine than the age-matched population tested in developing the SNN. In acutely ill patients with low Ucr, SNN overpredicted Clcr by 10-20 ml/min. SNN also overpredicted Clcr values in obese patients, but use of IBW rather than ABW improved the correlation between measured and predicted values in this subgroup. The SNN nomogram is applicable to critically ill patients if adjustments are made in predicted values. The characteristics of patients with low Ucr and the mechanism responsible for the decreased Ucr deserve further study.

Comparison of methods for estimating digoxin dosing regimens

Five methods of predicting serum digoxin concentrations (SDCs), used in conjunction with three equations for estimating creatinine clearance, were compared. Radioimmunoassay was used to determine the nadir SDCs in 79 patients (38 men, 41 women) meeting predetermined study criteria. All patients, whose ages ranged from 33 to 94 years, had steady-state digoxin levels, were on oral digoxin, and were free from thyroid dysfunction, malabsorption syndromes, dehydration, and renal failure. Three equations, involving combinations of age, lean body weight, and serum creatinine, were used to estimate creatinine clearance (Clcr). These Clcr values were then used in each of five equations to estimate SDCs. The estimated SDCs were compared to actual SDCs in the 79 patients, and the effects of changing the fraction of dose absorbed and the method of determining Clcr were analyzed. No substantial difference in predictive reliability was evident among the methods studied. Poor correlations existed between observed and calculated SDCs (r less than 0.70), and these correlations were not significantly affected by gender, fraction of dose absorbed, or method of Clcr estimation. Higher correlations were found for the oldest and youngest age groups. Severe limitations are associated with the use of the formulas studied.

Estimating creatinine clearance in children: Comparison of three methods

Three methods of estimating creatinine clearance (Clcr) in children were compared in pediatric patients ranging in age from 1 to 16 years. Sixty-eight measured Clcr determinations, normalized to ml/min/1.73 sq m of body surface area, were performed on 58 patients. Estimated Clcr values were calculated using the methods of Schwartz et al. (Method I), Shull et al. (Method II), and Rudd et al. (Method III), and each method was correlated with the measured creatinine clearance. Mean prediction error (estimated Clcr minus measured Clcr) also was compared for the methods to assess the relative prediction accuracy. Measured and estimated Clcr values correlated well (Method I, r = 0.90; Method II, r = 0.85; Method III, r = 0.80; p less than 0.0001). Mean prediction errors for Methods I and III (4.1 and -2.8 ml/min/1.73 sq m, respectively) were not significantly different; however, both methods were significantly more accurate (p less than 0.01) than Method II (mean prediction error: -17.4 ml/min/1.73 sq m). In this study, Method I, which was based on height and serum creatinine, was found to have the greatest accuracy and simplicity and to be the most clinically useful method of the three methods. The applicability of the three methods to pediatric patients with severe renal disease is uncertain.