Pharmacokinetics of ceftriaxone in subjects with renal insufficiency

The pharmacokinetics of ceftriaxone was studied in 14 men and women volunteers with renal insufficiency. Subjects were grouped by renal function: those with end-stage renal disease (CLcr less than 15 mL/min/1.73 sq m) but not receiving dialysis, those with severe renal insufficiency (CLcr 16-30 mL/min/1.73 sq m), and those with moderate renal insufficiency (CLcr 31-60 mL/min/1.73 sq m). Ceftriaxone 1 g as the sodium salt was administered by i.v. infusion over 30 minutes, and blood and urine samples were collected before and up to 48 hours after drug administration. The pharmacokinetic data were described using a nonlinear least-squares computer program. For volunteers with a creatinine clearance of less than 15 mL/min/1.73 sq m, the mean half-life was 15.6 hours. For subjects with a creatinine clearance of 31-60 mL/min/1.73 sq m, the mean half-life was 11.9 hours. Plasma ceftriaxone concentrations measured at the conclusion of the infusion (mean peak concentration 122 +/- 53.1 micrograms/mL) or 24 hours after the infusion (mean concentration 20.2 +/- 6.14 micrograms/mL) were similar in each study group. A dose of ceftriaxone 1 g every 24 hours in patients with renal insufficiency is probably adequate for inhibiting most susceptible gram-positive and gram-negative microorganisms.     

The effects of renal impairment on the pharmacokinetics and safety of fosfluconazole and fluconazole following a single intravenous bolus injection of fosfluconazole

AIMS: Fosfluconazole is a phosphate prodrug of fluconazole (FLCZ). This study was conducted to investigate the effect of renal impairment on the pharmacokinetics of fosfluconazole and FLCZ, and to assess the safety and toleration of fosfluconazole following a single intravenous bolus injection of fosfluconazole in subjects with normal and impaired renal function. METHODS: In an open, parallel-group, two-centre study, subjects with normal and impaired renal function received a single 1000-mg bolus intravenous injection of fosfluconazole. Subjects were categorized as Normal (> 80 ml min(-1)), Mild (51-80 ml min(-1)), Moderate (30-50 ml min(-1)) or Severe (< 30 ml min(-1)) impairment group according to their Cockcroft and Gault creatinine clearance (CLcr) values. Concentrations of fosfluconazole and FLCZ were determined in plasma and urine samples taken up to 240 h and 48 h postdose, respectively. RESULTS: Fosfluconazole plasma concentrations were very similar across the four groups, and there was no apparent relationship between any of the fosfluconazole pharmacokinetic parameters with increasing renal impairment. The conversion of fosfluconazole to FLCZ was unaffected by the degree of renal impairment. Only small amounts of fosfluconazole were excreted in the urine suggesting almost complete conversion to FLCZ. FLCZ concentrations were still detected in plasma after 240 h postdose and remained higher at the later sampling times in subjects in the Moderate and Severe groups. The area under the plasma concentration vs. time curve between time zero and infinity (AUC), the terminal elimination phase half-life (t(1/2)) and the mean residence time (MRT) of FLCZ all increased with the degree of renal impairment. The ratios (95% confidence interval) for AUC (Renal impairment group/Normal group) were 112.8% (89.5, 142.1), 240.6% (128.2, 451.4) and 355.1% (259.3, 486.3) for the Mild, Moderate and Severe impairment groups, respectively. There was a linear relationship between CLcr with AUC, t(1/2), MRT and the total plasma clearance of FLCZ (CL/F). Both the amount excreted over 48 h in the urine and the renal clearance of FLCZ decreased with an increase in renal impairment. The adverse events reported were mild to moderate in intensity, and there was no observed relationship with impairment group. There were no severe or serious adverse events, and in general fosfluconazole was well tolerated. CONCLUSIONS: The pharmacokinetics of fosfluconazole, including its efficient conversion into FLCZ, were unaffected by renal impairment. For FLCZ, there was a significant linear relationship between CLcr and AUC, t(1/2), MRT and CL/F, with AUC, t(1/2) and MRT increasing and CL/F decreasing as renal impairment increased. The dose adjustment used for FLCZ (half normal dose for patients with CLcr at 相似文献   

Effects of cilastatin sodium, an inhibitor of dehydropeptidase-I, on human urinary peptide excretion. Patients with renal insufficiency

Effects of imipenem/cilastatin sodium (IPM/CS), a new parenteral carbapenem combination antibiotic, on the excretion of urinary peptides were investigated by amino acid analysis of these peptides from 12 patients with varying degrees of impairment of renal function, after single or multiple doses (9 doses) of 500 mg/500 mg of the combination drug administered by 30-minute drip infusion. In a single dose study, slight increase in glycine (Gly) were observed in patients with mildly impaired renal function (group I). On the other hand, several amino acids including aspartic acid (Asp), glutamic acid (Glu), Gly and alanine (Ala) were increased in patients with moderately (group II) and severely (group III) impaired renal function. Gly showed the greatest increase, 1.029 microM/mg creatinine.2 hours, and the value was 2.4 times as high as the control collected before drug administration. These values were reduced to the control levels within 10-12 hours after the drug administration for amino acids showing small increases and within 12-24 hours after drug administration even for those showing greater increases. In a multiple-dose study employing 3 patients with moderately impaired renal function, Asp and Gly were found to increase after the 1st, 5th and 9th doses. The increased amino acids were reduced to preadministration levels within 10-12 hours or faster, and no tendency for accumulation was observed. From the above results, CS, as a dehydropeptidase-I inhibitor apparently caused increases in some peptides consisting mainly of Asp, Glu, Gly and Ala in patients with impaired renal function. A careful selection of dose levels and frequency of administration will be required in patients with moderately or severely impaired renal function.     

Pharmacokinetics of pregabalin in subjects with various degrees of renal function

The objectives of this study were to determine the single-dose pharmacokinetics of pregabalin in subjects with various degrees of renal function, determine the relationship between pregabalin clearance and estimated creatinine clearance (CLcr), and measure the effect of hemodialysis on plasma levels of pregabalin. Results form the basis of recommended pregabalin dosing regimens in patients with decreased renal function. Thirty-eight subjects were enrolled to ensure a wide range of renal function (CLcr < 30 mL/min, n = 8; 30-50, n = 5; 50-80, n = 7; and > 80, n = 6). Also enrolled were 12 subjects with renal impairment requiring hemodialysis. Each subject received 50 mg of pregabalin as two 25-mg capsules in this open-label, parallel-group study. Pregabalin concentrations were measured using previously validated liquid chromatographic methods. Pregabalin pharmacokinetic parameters were evaluated by established noncompartmental methods. Pregabalin was rapidly absorbed in all subjects. Total and renal pregabalin clearance were proportional (56% and 58%, respectively) to CLcr. As a result, area under the plasma concentration-time profile (AUC) and terminal elimination half-life (t1/2) values increased with decreasing renal function. Pregabalin dosage adjustment should be considered for patients with CLcr < 60 mL/min. A 50% reduction in pregabalin daily dose is recommended for patients with CLcr between 30 and 60 mL/min compared to those with CLcr > 60 mL/min. Daily doses should be further reduced by approximately 50% for each additional 50% decrease in CLcr. Pregabalin was highly cleared by hemodialysis. Supplemental pregabalin doses may be required for patients on chronic hemodialysis treatment after each hemodialysis treatment to maintain steady-state plasma pregabalin concentrations within desired ranges.     

Pharmacokinetics of intravenous, single-dose tiotropium in subjects with different degrees of renal impairment

Tiotropium, a new potent anticholinergic bronchodilator, is excreted mainly by the kidney. To investigate the pharmacokinetics of tiotropium in renal impairment, the authors evaluated the pharmacokinetics and safety after administration of a single dose of intravenous tiotropium 4.8 microg, given as an infusion over 15 minutes in subjects with normal renal function and a wide range of renal impairment based on measured creatinine clearance (normal: > 80 mL/min, n = 6; mild impairment: > 50-80 mL/min, n = 5; moderate impairment: 30-50 mL/min, n = 7; severe impairment: < 30 mL/min, n =6). As expected for a drug excreted predominantly in unchanged form by the kidneys, tiotropium plasma concentrations increased as renal impairment worsened, with mean values of 55.5 (16.2 percent geometric coefficient of variation [%gCV]), 77.1 (20.1 %gCV), 101 (29.8 %gCV), and 108 (27.3 %gCV) pgh/mL for AUC(0-4h) in the normal renal function and the mild, moderate, and severe renal impairment groups, respectively. The percentage of tiotropium dose excreted unchanged in the urine decreased from 60.1% of dose (17.7 %gCV) to 59.3% (14.4 %gCV), 39.9% (34.5 %gCV), and 37.4% (10.2 %gCV) in the normal renal function and the mild, moderate, and severe renal impairment groups, respectively. Plasma protein binding of tiotropium did not significantly change in the renal-impaired subjects. Two subjects with normal renal function experienced headache 10 hours after the infusion, which was mild and transient. No adverse events occurred in subjects with renal impairment. There were no clinically relevant changes in blood pressure, pulse rate, 12-lead ECG, physical examination, hematology, or clinical chemistry, compared with baseline values, in any subject after intravenous administration of tiotropium. Tiotropium should only be used in patients with moderate to severe renal insufficiency if the potential benefit outweighs the potential risks.     

Pharmacokinetics of cadralazine and its hydrazino-metabolite in patients with renal impairment after repeated administration of 5 mg once daily.

Since the hydrazino-pyridazine metabolite of cadralazine, CGP 22 639 is believed to contribute to the activity of the drug, its pharmacokinetics and that of cadralazine were investigated in 8 hypertensive patients with renal impairment. The creatinine clearance (CLcr) of patients ranged from 10 to 60 ml/min. The concentrations of cadralazine in plasma and urine, and of CGP 22 639 (plus its possible hydrazones) in plasma were measured after single and repeated administration of 5 mg of cadralazine once daily. A hypotension possibly linked to cadralazine treatment was recorded on day 3 for the patient with CLcr = 10 ml/min. Metabolite concentrations were found to be at least twice as high as in other patients indicating that in this patient, the daily dose of 5 mg was probably too high. The pharmacokinetics of cadralazine were not modified by repeated administration. The drug and its metabolite were eliminated more slowly in patients with low creatinine clearance. The t1/2 of CGP 22 639 was about twice the t1/2 of the unchanged drug. In patients whose CLcr ranged from 19-37 ml/min the mean accumulation factor of apparent CGP 22 639 was 1.7 times that of the unchanged drug. It shows that the apparent CGP 22 639 accumulated more than the unchanged drug. A starting daily dose of 2.5 mg of cadralazine in patients with CLcr < 40 ml/min appears to be suited to take into account the pharmacokinetics of CGP 22 639. This dose can be increased by 2.5 mg steps if the antihypertensive effect is not sufficient (maximum dose with CLcr < 40 ml/min: 10 mg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and pharmacodynamics of pegfilgrastim in subjects with various degrees of renal function

A phase I study was conducted to evaluate the effects of renal function on the pharmacokinetics and pharmacodynamics (absolute neutrophil count [ANC]) of pegfilgrastim in nonneutropenic subjects. Thirty subjects categorized into 5 renal function groups (normal, mildly impaired, moderately impaired, severely impaired, and end-stage renal disease) received 1 subcutaneous injection of pegfilgrastim at 6 mg. The ANC profiles after pegfilgrastim administration were similar across different renal function groups. No discernable correlation between pharmacokinetic parameter values and degree of renal impairment was observed; the mean values ranged from 147 to 201 ng/mL for C(max) and from 7469 to 8513 ng x h/mL for AUC. Results suggest that the kidney has no important role in the elimination of pegfilgrastim. Therefore, no dosage adjustment for renal impairment is indicated for pegfilgrastim.     

Pharmacokinetics and renal excretion of desmopressin after intravenous administration to healthy subjects and renally impaired patients

OBJECTIVE: To evaluate the influence of renal impairment on the pharmacokinetics of desmopressin. METHODS: Twenty-four subjects were enrolled in the study, 18 with varying degrees of renal impairment and six healthy volunteers. Each subject received a single intravenous dose of 2 microg desmopressin. Blood and urine samples were collected for 24 h and assayed for desmopressin by radioimmunoassay. Plasma concentrations and the amounts of desmopressin excreted in the urine were analysed simultaneously by use of mixed effects modelling. RESULTS: Only mild adverse events were observed. Both the renal and the nonrenal clearance of desmopressin were found to vary with the creatinine clearance (CrCL). A decrease of 1.67% in the CrCL (corresponding to 1 ml min(-1) from 60 ml min(-1)) was found to cause a 1.74% decrease in the renal clearance and a 0.93% decrease in the nonrenal clearance. The fall in renal clearance caused the amount of desmopressin excreted in urine to decrease from 47% in healthy subjects to 21% in the patients with severe renal impairment. The mean systemic clearance of desmopressin was 10 litres h(-1) in healthy subjects and 2.9 litres h(-1) in patients with severe renal impairment (difference -7.5 litres h(-1), 95% CI [-11; -4.3] litres h(-1)). Correspondingly, the mean terminal half-life, was 3.7 h in healthy subjects and 10 h in patients with severe renal impairment (difference 6.7 h, 95% CI [4.0; 9.4] h). CONCLUSION: Although desmopressin appears to be safe and well-tolerated by patients with impaired renal function, great caution should be exercised when titrating towards an efficient dosage regimen if patients with moderately or severely impaired renal function are to be treated with desmopressin at all.     

Pharmacokinetics of aspoxicillin in subjects with normal and impaired renal function

The pharmacokinetics of aspoxicillin [2S,5R,6R)-6-[(2R)-2-[(2R)-2-amino-3-(methylcarbamoyl)propionam ido]-2- (p-hydroxyphenyl)acetamido]penicillanic acid) in 10 subjects with normal kidney function and in 20 patients suffering from impaired renal function were examined after an i.v. short-term infusion of 4 g for a period of 20 min. In contrast to available semi-synthetic penicillins, aspoxicillin shows a slightly longer half-life elimination. As the substance is mainly excreted renally, the areas under the curve (AUC) are larger in cases of impaired renal function. Mathematical correlations can be established between the AUC and the renal function parameters creatinine and glomerular filtration rate. Dosage reduction factors are then derived which allow appropriate dosages to be established for the substances under examination. Dosages for differing degrees of impaired renal function are given in tables. Since sufficiently high and long-lasting urine levels are achieved, it is reasonable to use aspoxicillin as treatment of urinary tract infections in patients suffering from end-stage renal failure.     

血清肌酐正常的2型糖尿病患者肾小球滤过率水平与危险因素分析

目的 分析2型糖尿病(T2DM)患者的肾小球滤过率(glomerular filtration rate,GFR)异常与相应临床表现特点、主要危险因素,探讨临床观察和预防肾功能异常的关键点.方法 连续收集非急性并发症入院血清肌酐正常的T2DM患者381例,利用99mTc标记的二乙三胺五乙酸(99mTc-DTPA)肾动脉显像检测GFR,根据检测值范围分为:GFR≥90 mL·min-1为正常组,GFR≥60~90 mL·min-1为轻度异常组,GFR≥30~60 mL·min-1为中度异常组,对各组进行病史分析、体格检查、生化检查等,了解各组的临床指标特点与主要危险因素.结果 在入选的血清肌酐正常的T2DM患者中,GFR正常的占48.0%、轻度异常占40.8%、中度异常占11.2%;应用有序logistic(Ordinal)等级回归显示,性别、年龄、糖尿病病程、糖化血红蛋白(HbA1c)、血肌酐、尿 α1微球蛋白、尿肌酐、尿蛋白与尿肌酐比值是显著影响GFR的因素(β值分别为0.076、0.048、0.023、0.051、0.454、-0.072、0.324、-0.911,均P<0.05),校正影响因素发现GFR主要与HbA1c、血肌酐、尿蛋白有关.结论 血清肌酐正常的T2DM患者的GFR降低影响因素主要与高血糖有关,预防肾脏病变主要还是控制血糖,同时也要防止尿蛋白的出现.     

The pharmacokinetics of remoxipride and metabolites in patients with various degrees of renal function.

1. The pharmacokinetics of remoxipride, a new neuroleptic, were investigated in an open study with three parallel groups. Twenty-one patients with severely impaired (ClCr < 25 ml min-1), moderately impaired (ClCr 25-50 ml min-1) and normal (ClCr > 65 ml min-1) renal function were evaluated. A single oral dose of remoxipride hydrochloride 100 mg was administered, and blood and urine were collected over 48 h. Concentrations of remoxipride and metabolites were measured by h.p.l.c. 2. In patients with severely decreased renal function, the AUC and Cmax of remoxipride were increased significantly, and t1/2 was prolonged, as compared with the control patients. The renal clearance and urinary recovery of the unchanged drug were significantly diminished. 3. The unbound fraction of remoxipride in plasma was decreased in patients with renal failure, in association with a disease-related increase in alpha 1-acid glycoprotein. In spite of a 25% recovery of unchanged drug in the urine in patients with normal renal function, the AUC of unbound drug was twice as high in patients with severely impaired renal function. 4. A strong correlation between creatinine clearance and renal drug clearance was observed indicating a direct relationship between kidney function and the renal clearance of remoxipride. 5. Remoxipride was the predominant compound in plasma as well as in urine in patients with severely decreased as well as normal renal function. In patients with severely decrease renal function, remoxipride and all five pharmacologically inactive metabolites showed increased peak plasma concentrations, delayed tmax, increased AUC, prolonged half-lives and decreased renal clearance.     

Clinical pharmacokinetics of bezafibrate in patients with impaired renal function

Summary The pharmacokinetics of the new lipidlowering drug bezafibrate has been investigated in patients with impaired renal function and hyperlipoproteinaemia. 12 patients received a single oral dose of bezafibrate 300 mg. Plasma and urine samples were collected and bezafibrate was analyzed by gas chromatography. Eight of the patients had moderately impaired renal function, with a creatinine clearance between 20 and 40 ml/min; the mean plasma half-life of bezafibrate in them was 7.8±3.9 h (SD) and the plasma clearance was 0.03±0.02 l/kg · h. Three of the patients had a creatinine clearance>40 ml/min; in them the plasma half-life was shorter, 4.6±1.2 h, and the plasma clearance was higher, 0.06±0.01 l/kg · h. The slowest elimination of bezafibrate was found in a patient with a creatinine clearance of only 13 ml/min. This patient had a plasma half-life of 20.1 h, which is ten times longer than has been reported in healthy volunteers. Thus, when treating hyperlipoproteinaemia in patients with impaired renal function, the dosage of bezafibrate must be individualized because of its reduced renal elimination.     

Clinical pharmacology and efficacy of levofloxacin in elderly patients]

We studied a newly developed oral quinolone antimicrobial agent, levofloxacin (LVFX, DR-3355), and obtained the following results. 1. Serum and urine levels of LVFX were determined after oral administration of LVFX 100 mg to 11 elderly patients with various degrees of renal function insufficiencies. The patients were classified according to creatinine clearance (Ccr) values into Group I (n = 1, Ccr greater than or equal to 70 ml/min), Group II (n = 4, 40 less than or equal to Ccr less than 70 ml/min), and Group III (n = 6, Ccr less than 40 ml/min). The peak levels of LVFX did not differ greatly among the 3 groups, but in patients with severely impaired renal functions, serum concentrations decreased more slowly than in those with slightly and moderately impaired renal functions, and high serum levels were maintained over a long period. Urinary excretion of LVFX diminished in relation to degrees of renal failure. 2. LVFX was administered to treat 13 elderly patients with respiratory tract infections. Clinical responses were good in all patients with a high efficacy rate of 100%. Laboratory tests revealed eosinophilia in 1 case. The symptom was mild, however, and no severe side effects due to the drug were observed.     

Pharmacokinetics of oxiracetam in patients with renal impairment after a 800 mg single oral dose

The pharmacokinetics of oxiracetam in patients with renal impairment were investigated after administration of a 800 mg single oral dose of oxiracetam. The renal insufficiency was estimated on the basis of the creatinine clearance (CLcr) which ranged from 9 to 95 ml/min among the 20 patients. In plasma, the terminal elimination half-life (T1/2) ranged from 10.6 to 68.1 h, the highest T1/2 corresponding to the patients with a high degree of renal impairment. In urine, the amounts of oxiracetam excreted during the 48 h postdosing represented 8.3 to 82.6% of the dose. They were lower in patients with a high degree of renal impairment. The correlations between the total clearance of oxiracetam, the renal clearance, the terminal apparent elimination rate constant in plasma, and CLcr were estimated by linear regression analysis. The correlation coefficients were 0.916, 0.985 and 0.803 respectively. The apparent volume of distribution of the central compartment V(1) and the total volume of distribution at the steady-state V(SS) were not dependent on the degree of renal impairment. The mean values +/- SD were 25.9 +/- 13.0 litres and 48.3 +/- 21.5 litres respectively. Oxiracetam concentrations in plasma of patients were estimated for repeated administration of 800 mg of oxiracetam.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disposition of etofibrate, clofibric and nicotinic acid esters, and their products in dogs

Etofibrate, the ethylene glycol diester of clofibric and nicotinic acids, on intravenous infusion into dogs, has a terminal half-life of 2 min. The intermediate half-esters, the nicotinate and the clofibrate, have respective terminal half-lives of 4.6 and 1.7 min and appear fleetingly when etofibrate is administered. In contrast to the 42-h terminal half-life of clofibric acid, the other final transformation product, nicotinic acid, shows saturable or dose-dependent pharmacokinetics in dogs that conform to the Michaelis-Menten equation with a terminal half-life of 4.4 min at low concentrations (less than 6.9 microM/kg). Three distinct metabolites of nicotinic acid can be identified and assayed chromatographically in the urine. The partition properties were similar to nicotinic acid. Nicotinic acid is excreted 30% unchanged into urine with a renal clearance of 70 mL/min in 27-kg dogs.     

雷米芬太尼及其主要代谢物雷米芬太尼酸在术后镇痛患者中的药动学研究

目的:研究雷米芬太尼(R)及其体内的主要代谢产物雷米芬太尼酸(RA)在开胸手术后镇痛患者中的药动学,为临床合理安全用药提供依据。方法:20例成年患者纳入本项研究,其中包括肾功能正常者10例(CLcr(72.1±11.5)mL·min-1,n=10),中/重度肾功能损害者10例(CLcr(27.9±14.7)mL·min-1,n=10)。R静脉滴注速度为6μg·kg-1·h-1,持续72h,用药后收集72h内的桡动脉血样本,计算药动学参数。结果:R的药动学在正常组与中/重度肾功能损害组间无显著性差异;在中、重度肾功能损害组,RA的肾清除率下降为正常组的约25%((41.2±16.1)vs.(157±19.5)mL·h-1·kg-1,P<0.001)。R血药浓度达到稳态时,中/重度肾功能损害者对R的代谢比大约为正常者的8倍((115±39.3)vs.(14.3±5.4),P<0.001)。在中/重度肾功能损害者体内,RA的最高浓度接近200ng·mL-1,但未达到产生阿片类药效的血药浓度。结论:肾功能状态对R药动学参数无显著影响;但肾功能受损时,RA在体内易产生蓄积。     

Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate

OBJECTIVE: Antiepileptic drugs are often used in patients with some degree of renal impairment. The objective of this study was to evaluate the effect of renal function on the pharmacokinetics of eslicarbazepine acetate (ESL, formerly known as BIA 2-093), a new antiepileptic drug under clinical development. METHODS: ESL pharmacokinetics following 800 mg single dose was characterized in subjects with normal renal function (n=8, control group), and in patients with mild renal impairment (n=8), moderate renal impairment (n=8), severe renal impairment (n=8), and end-stage renal disease requiring hemodialysis (n=8). RESULTS: ESL suffered extensive first-pass hydrolysis to eslicarbazepine (S-licarbazepine), the main active metabolite. While eslicarbazepine Cmax did not significantly differ between the different groups, the extent of systemic exposure, assessed by AUC, increased when renal function decreased. Eslicarbazepine CL/F and CLR were, respectively, 3.40 l/h and 1.04 l/h (17.3 ml/min) in the control group, and 2.10 l/h (35.0 ml/min) and 0.61 l/h (10.2 ml/min) in the mild, 1.60 l/h (26.7 ml/min) and 0.22 l/h (3.7 ml/min) in the moderate, and 1.33 l/h (21.2 ml/min) and 0.09 l/h (1.5 ml/min) in the severe renal impairment groups. Although the total amount of eslicarbazepine recovered in urine until 72 h post-dose was similar in the control and mild renal impairment groups, a decrease was found in the moderate and severe renal impairment groups. Major metabolites recovered in urine were eslicarbazepine and its glucuronide form. Clearance of minor metabolites (R-licarbazepine, oxcarbazepine and their glucuronides) was also dependent on renal function. In patients with end-stage renal disease, dialysis was effective in removing the ESL metabolites from the circulation. CONCLUSIONS: ESL metabolites are excreted primarily by renal route and their clearance is dependent on renal function. ESL dosage adjustment may be necessary in patients with a creatinine clearance <60 ml/min.     

Comparison of bioavailability and pharmacokinetics of cimetidine in subjects with normal and impaired renal function

The bioavailability and pharmacokinetics of cimetidine were studied following single oral and intravenous doses in subjects with severely impaired renal function (SIRF) and normal renal function (NRF). Eight subjects with NRF and five patients with SIRF participated. Multiple blood samples were obtained up to 1440 minutes following both doses. Urine was also collected for 24 hours after each dose. The bioavailability of cimetidine was not significantly different between the two groups (78 +/- 15% in patients with SIRF and 62 +/- 17% in the NRF subjects). In subjects with NRF, a mean of 50.4% of the i.v. dose was excreted renally as unchanged drug and the mean serum half-life (t1/2) was 2.00 hours. The mean total body and renal clearances were 710.0 and 370.7 ml/min, respectively. In the SIRF group, a mean of 1.7% of the i.v. dose was excreted renally unchanged, and the mean t1/2 was 12.71 hours. The total body and renal clearances were 147.1 and 2.5 ml/min, respectively. Nonrenal clearance was 62% lower in the subjects with SIRF than in the NRF subjects. There is no significant difference in bioavailability of cimetidine between the patients with NRF and SIRF. The significantly lower nonrenal clearance of the patients with SIRF suggests that cimetidine metabolism may be impaired in uremic patients.     

Cefaclor dosage change with renal dysfunction

Serum and/or urine levels of cefaclor (CCL) were studied in 4 patients during the therapy with CCL. In patients with severely impaired renal function, moderately higher serum and urine levels of CCL persisted, serum half-lives of CCL were moderately prolonged and urinary excretion of CCL slightly decreased. Although dosage modification of CCL is necessary in patients with renal dysfunction, multiple doses of 250 mg every 8 hours may be safe and effective even in patients with impaired renal function.     

Effects of impaired renal function on the pharmacokinetics and toxicity of i.v. ZD9331, a novel non-polyglutamated thymidylate synthase inhibitor,in adult patients with solid tumors

ZD9331 is a potent thymidylate synthase inhibitor. Renal and hepatic clearances were found to be important routes of elimination. The objectives of this pharmacologic trial were to investigate the effect of renal impairment on the pharmacokinetics of ZD9331, to study the toxicity profile and to document any antitumor effects of ZD9331 when administered i.v. to patients with different degrees of renal impairment. Patients were treated with ZD9331 130 mg/m2 given as an i.v. infusion on day 1 of a 4-week cycle to allow full pharmacokinetic assessment. Subsequent cycles involved the administration of ZD9331 on days 1 and 8, every 3 weeks. Patients were stratified according to their renal function assessed by the creatinine clearance: normal renal function (creatinine clearance > or =60 ml/min), mildly impaired renal function (creatinine clearance > or =40 to <60 ml/min) and moderately impaired renal function (creatinine clearance >25 to <40 ml/min). For pharmacokinetic analysis plasma sampling was performed during the first course and assayed using a validated liquid chromatographic tandem mass spectrometry assay. Twenty-three patients were entered on the study, of whom 21 received 130 mg/m2 ZD9331 in the first treatment cycle. No relationship was seen between renal impairment and plasma clearance nor with the area under the concentration-time curve of free ZD9331. Increasing renal impairment was associated with a greater incidence of myelosuppression. No predictive relationship between the clearance of free ZD9331 and the degree of renal impairment as determined by creatinine clearance could be assessed. However, data from this trial indicate that increased renal impairment may be associated with greater ZD9331-induced toxicity, particularly myelosuppression, although this cannot be attributed to any alteration in the plasma pharmacokinetics of ZD9331. Therefore, it may be necessary to administer a reduced dose of ZD9331 to patients with impaired renal function.