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.     

Pharmacokinetics of glucarpidase in subjects with normal and impaired renal function

Glucarpidase (formerly known as carboxypeptidase G2 or CPG2) is being evaluated for the adjunctive treatment of patients experiencing, or at risk of, methotrexate toxicity attributable to its delayed elimination. Delayed elimination of methotrexate can occur in patients with methotrexate-induced renal toxicity. In this study, glucarpidase pharmacokinetics were assessed in volunteer subjects with normal (n = 8) and severely impaired (n = 4) renal function. Each subject received a single intravenous dose of glucarpidase 50 U/kg (equivalent to 114.5 microg/kg) infused over 5 minutes. The mean maximum serum concentration (C(max)) for glucarpidase in renally impaired subjects was 2.9 microg/mL, the mean half-life (t(1/2)) was 10.0 hours, and the mean area under the serum concentration-time curve from time zero to infinity (AUC(0-infinity)) was 24.5 microg x h/mL. Similar values were found in subjects with normal renal function (mean C(max) 3.1 microg/mL, mean t(1/2) 9.0 hours, and mean AUC(0-infinity) 23.4 microg x h/mL). The results indicated little effect of renal impairment on the serum pharmacokinetics of glucarpidase.     

Pharmacokinetics of naproxen in subjects with normal and impaired renal function

Summary The pharmacokinetics of naproxen after a single oral dose of 250 mg has been studied in 8 subjects with normal renal function and 16 patients with varying degrees of chronic renal insufficiency. Unchanged naproxen and its main unconjugated metabolite, 6-0-desmethylnaproxen, were determined fluorometrically in serum. In healthy subjects the elimination half-life of naproxen was 17.7± 3.0 h (mean±SD) and it was not significantly prolonged in patients with renal failure (18.1±5.3) h. No accumulation of naproxen in serum occurred in uraemic patients. On the contrary, serum drug levels were slightly but significantly lower in patients with severe renal failure. The total body clearance and apparent volume of distribution of naproxen were significantly increased in this group of patients. Decreased binding of naproxen to serum proteins was observed in patients with renal failure. The apparent half-life of desmethylnaproxen was of the same order of magnitude as that of naproxen (18.6± 4.4 h), and was also independent of renal function. A good correlation was found between the area under the curve (AUC), the peak concentration of the metabolite and the serum creatinine concentration. These observations suggest increased metabolism and an increased apparent volume of distribution of naproxen in severe renal failure, probably caused by decreased serum protein binding of the drug. However, it is proposed that in naproxen therapy no adjustment of the dosage regimen is necessary in patients with impaired renal function.     

Steady-state pharmacokinetics of nefazodone in subjects with normal and impaired renal function

The steady-state pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were compared in subjects with normal and impaired renal function. Patients: The Study was of parallel group design which included 7 subjects with normal (NOR) renal function, CL_CR72 ml·min^–1·1.73 m^–2, 6 with moderate (MOD) renal impairment, CL_CR 31–60 ml·min^–1·1.73 m^–2 and 9 with severe (SEV) renal impairment, CL_CR30 ml·min^–1·1.73 m^–2. Subjects in each renal function group received a 100-mg oral dose of nefazodone hydrochloride BID for 7 days and a single morning dose on day 8. Starting 48 h after the last 100-mg dose, 200-mg doses were administered on a similar schedule to 3, 4 and 3 subjects from each renal function group (NOR, MOD and SEV, respectively). Single trough blood samples just prior to each morning dose (C_min) and serial samples after the dose on day 8 were obtained at each dose level for pharmacokinetic analysis. Plasma samples were assayed by a specific HPLC method for NEF, HO-NEF and mCPP.The CMIN data indicated that steady state was attained by the third day of BID administration of both the 100- and 200-mg doses of nefazodone, regardless of degree of renal function. Both NEF and HO-NEF attained steady-state C_max within 2 h after administration of nefazodone; t_max for mCPP was less defined and more delayed. HO-NEF and mCPP plasma levels were about 1/3 and <1/10 those of NEF, respectively, regardless of the status of renal function. Steady-state systemic exposure of NEF and HO-NEF, as reflected by AUC and C_max, and elimination t_1/2 values did not differ significantly among renal function groups. Conclusion: The study results suggest that dose adjustments may not be necessary, but nefazodone should be used with caution in the presence of severe renal impairment.     

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.     

The concentration-dependent disposition of intravenous p-aminohippurate in subjects with normal and impaired renal function.

1. The disposition and kinetics of p-aminohippuric acid (PAH) were studied in 27 healthy male volunteers, 10 healthy female volunteers and 10 patients with chronic renal impairment following rapid intravenous injection of 10 mg kg-1. In addition, the renal clearances of PAH and its metabolite N-acetyl-PAH were measured in 10 of the healthy male volunteers following conventional administration of PAH by loading dose and constant infusion, and in another eight during sequential 'step-up' and 'step-down' infusions intended to maintain low, medium and high plasma concentrations below the threshold for onset of saturation of tubular transport. 2. PAH was eliminated rapidly with a mean half-life of less than 30 min in the healthy volunteers and 72 min in the renal patients. The corresponding estimates for acetyl-PAH were 49 and 153 min. In both groups the rate of disappearance of PAH slowed progressively over the period of observation and there was no true log-linear terminal elimination phase. 3. In the healthy volunteers about 50% of the dose was excreted in the urine in 30 min with quantitative recovery in 3 h. In 8 h, 17% of the dose was recovered as acetyl-PAH. In the patients with renal impairment the 8 h recovery was only 83.6% of the dose with 26.9% of the total appearing as acetyl-PAH. 4. The volume of distribution (Vss) of PAH was 16-18 l in the healthy subjects and renal patients. Acetyl-PAH appeared to have a much larger distribution volume (mean 65.5 l in the healthy volunteers). 5. In the healthy volunteers the renal clearance of PAH fell dramatically from 599 +/- 115 ml min-1 1.73m-2 during the first hour after administration to 300 +/- 208 ml min-1 1.73 m-2 during the second hour (P < 0.001). The corresponding renal clearances of acetyl-PAH were 775 +/- 196 and 916 +/- 212 ml min-1 1.73 m-2. In the patients with renal impairment the renal clearance of PAH fell from 194 +/- 83 ml min-1 1.73 m-2 in the first hour to only 61 +/- 19 ml min-1 1.73 m-2 from 4 to 6 h. Over the same period there was no significant fall in the clearances of acetyl-PAH or total PAH (acetyl-PAH + PAH).(ABSTRACT TRUNCATED AT 400 WORDS)     

Disposition of the cephalosporin cefepime in normal and renally impaired subjects.

The metabolism and disposition of an iv-administered, 1000 mg (100 microCi) single dose of the 14C-labeled cephalosporin cefepime was studied in healthy and renally impaired male volunteers. The 14C-label was located in the methyl group of the N-methyl pyrrolidine (NMP) moiety at the 3'-position of cefepime. Concentrations of cefepime and its metabolites were determined in plasma and urine as a function of time after drug administration. Cefepime comprised 95 and 76% of the total plasma radioactivity in subjects with normal and impaired renal functions, respectively. The elimination half-life of cefepime was 2 hr in normal volunteers and increased to 4 and 12 hr in subjects with moderate and severe renal impairment, respectively. Steady-state volume of distribution was about 18 liters and was independent of the degree of renal impairment. Cefepime was primarily excreted unchanged in the urine of normal subjects, as 87.9% of the total recovered radioactivity. The major cefepime metabolites, NMP N-oxide, the 7-epimer of cefepime and NMP, constituted 6.8, 2.5, and less than 1% of the total radioactivity excreted in urine, respectively. As the severity of renal impairment increased, the proportion of radioactivity recovered in urine as cefepime decreased and that of NMP-N-oxide increased. Our results indicate that cefepime undergoes minimal metabolism and is excreted primarily as unchanged drug in urine in humans with normal kidney functions.     

Regadenoson pharmacokinetics and tolerability in subjects with impaired renal function

The authors have investigated the pharmacokinetics and tolerability of regadenoson, a selective A2A adenosine receptor agonist for use in drug-stressed myocardial perfusion imaging in subjects with varying degrees of renal function. Sixteen subjects with different creatinine clearance values (range: 15-132 mL/min) received a single intravenous bolus dose of 400 microg regadenoson. A population pharmacokinetic model was developed to describe the pharmacokinetics of regadenoson in these subjects. Regadenoson elimination half-life was prolonged with decreasing renal function. However, maximum plasma concentrations, number, or severity of adverse events did not differ significantly between the subjects. Heart rate increased in all subjects after regadenoson injection but returned to normal within 150 minutes. There were no blood pressure pattern differences with respect to renal function. Results from this study do not indicate that dose adjustments are necessary when subjects with decreased renal function are administered the clinically relevant dose of 400 microg regadenoson.     

Raloxifene pharmacokinetics in males with normal and impaired renal function

AIMS: To compare raloxifene pharmacokinetics between renally impaired and healthy subjects. METHODS: Raloxifene 120 mg was administered to 10 males with renal impairment (creatinine 2-4 mg dl(-1)) and to 10 healthy males. Data were analysed by two noncompartmental and one compartmental nonlinear regression methods. RESULTS: The medians (95% confidence interval) of the area under the curves (AUC) were 35.1 (25.8, 74) and 20.5 (16.8, 28.0) h ng ml(-1) per mg kg(-1), P < 0.01, and of the clearances (CL/F) were 28.5 (13.5, 38.8) and 48.8 (35.8, 59.4) l h(-1) kg(-1), P < 0.01, in renally impaired and healthy subjects, respectively. 95% Confidence intervals on the differences for AUC and CL/F were 6.5-44.1 and -35.1 to -7.9, respectively. CONCLUSION: Exposure to raloxifene was twice as high in males with renal impairment compared with healthy subjects.     

Pharmacokinetics of nicorandil in patients with normal and impaired renal function

Summary The pharmacokinetics of oral nicorandil 20 mg 12 hourly for 9 doses was evaluated in 21 hospitalized patients with angina pectoris due to coronary heart disease and with normal and impaired renal function. Patients were divided into 3 groups based on creatinine clearance (CL_Cr): GROUP I (n=6) > 80 ml/min, GROUP II (n=8) 20–80 ml/min, and GROUP III (n=7) < 20 ml/min.After the first dose, the total clearance of nicorandil (CL) value did not change with increasing renal failure and so was not dependent on creatinine clearance. After the last dose CL was 51 l·h^–1 in Group I, 44 l·h^–1 in Group II and 56 l·h^–1 in Group III, and it was not related to creatinine clearance. The percentage of the dose excreted in the urine was 0.4%. No significant difference was noted in any of the other pharmacokinetic parameters examined in the three groups, not even on comparing values obtained on the first and last days of treatment.The findings suggest that there is no need to change the dose of nicorandil in subjects with different degrees of renal failure.     

Pharmacokinetics of Cefmenoxime in normal and impaired renal function

7 beta-[2-(2-Aminothiazol-4-yl)-(Z)-2-methoxy-iminoacetamido]-3-[(1- methyl-1H-tetrazol-5-yl)thiomethyl]-ceph-3-em-4-carboxylic acid hemihydrochloride (Cefmenoxime), a new cephalosporin with a broad spectrum of activity against gram-positive and gram-negative bacteria, was investigated pharmacokinetically. 10 healthy volunteers and 20 patients with renal disease each received 2 g of the substance i.v. The plasma levels were monitored for 6 h in healthy volunteers and for 24 h in the patients with renal disease. The analysis of the data showed that the majority of the curves could be properly evaluated only with the aid of a two-compartment model. Therefore a simple half-life cannot be given. Cefmenoxime is eliminated more rapidly than cefoperazone, but more slowly than cefotaxime. The area under the serum level curves (AUC) increases when renal function is impaired. There is a mathematical correlation between the AUC and the renal function parameters, plasma creatinine and glomerular filtration rate. This gives the dose reduction factors, allowing the calculation of the doses with the same AUC on restricted renal function as that observed in healthy persons after normal doses. Dosage recommendations are given in the form of tables regarding the questions 1. to what extent the dose may be reduced in impaired renal function without lowering the AUC and 2. what is the highest safe dose.     

Pharmacokinetics of pefloxacin in normal and impaired renal function

Ten healthy young volunteers (mean age 28 years) and 24 patients (mean age 54 years) suffering from various degrees of chronic renal failure received an infusion of 400 mg pefloxacin (1-ethyl-6-fluoro-1, 4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid) over 30 min. The blood and urine levels of pefloxacin and of the two metabolites pefloxacin-N-oxide and norfloxacin were determined using the HPLC method. Blood levels were taken after periods of 0, 60, 120, 180, 360, 600, 720, 1440, 2880, 3360 min, and in patients suffering from renal insufficiency also after 4320 min. The urine was collected and analyzed during the periods of 0-2, 2-4, 4-10 (12) h and then in longer periods up to 72 h. In all subjects, the glomerular filtration rate (GFR, by chrome-51-EDTA) and the plasma creatinine level were determined. Effective levels against bacteria lying in pefloxacin's spectrum can be found in the plasma for about 1.5 days and in the urine for about 2.5 days. Patients suffering from chronic renal failure have pefloxacin plasma levels which beyond 24 h are higher than in healthy persons. This can be explained by both: impaired renal and extrarenal elimination. The volume of distribution of the volunteer and the patient group does not differ significantly. Therapeutic urine levels could be found in patients up to 48 h after end of infusion. Even in patients requiring regular hemodialysis, therapeutic urine levels were found up to 24 h (if urine could be produced at all). The substance therefore is a suitable remedy for urinary infections in dialysis patients as well.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic comparison of flurbiprofen in end-stage renal disease subjects and subjects with normal renal function.

This study compared the pharmacokinetics of flurbiprofen (F) and three major metabolites in patients with end-stage renal disease (ESRD) undergoing continuous ambulatory peritoneal dialysis (CAPD) with the pharmacokinetics of F in normal subjects. A single 100-mg dose of F was administered to each of nine normal subjects and eight ESRD subjects. Blood and urine samples were collected in both groups; serial and end of dwell dialysate samples were obtained from the ESRD subjects. Plasma was analyzed for both the R and S optical isomers of F and its major metabolite, 4'-hydroxy-flurbiprofen (HF). Urine and dialysate were analyzed for F and three known metabolites. Plasma concentrations of F in the ESRD subjects were approximately 50% of the values obtained from the normal subjects (P less than .05). Flurbiprofen half-life and Tmax were not different. Elimination of HF was reduced in ESRD subjects. Urinary data suggest that HF was the major metabolite excreted (36% of the dose) in normal subjects whereas 3',4'-dihydroxy-flurbiprofen was the major metabolite (9% of the dose) excreted in the ESRD group. Mean urinary recovery of the dose was 73% in the normal subjects, but only 16% in ESRD subjects. Neither F nor its metabolites were detected in dialysate. Small enantiomer differences were seen. This study suggests that ESRD subjects have lower plasma levels of F than normal subjects when administered equal size doses. Accumulation of metabolites may occur in ESRD subjects upon multiple dosing. Enantiomer differences are not clinically significant.     

Pharmacokinetics of lisinopril in hypertensive patients with normal and impaired renal function

Summary The pharmacokinetics of lisinopril was studied after administration of single and multiple doses of 5 mg to hypertensive patients with normal and impaired renal function.In patients with severe renal failure the peak concentrations were higher, the decline in serum concentration was slower and the time to peak concentration was extended. Accumulation of lisinopril was highly correlated with the creatinine clearance. The effective half-life was doubled and tripled in patients with mild and severe renal impairment, respectively, as compared to patients with a normal renal function. Lisinopril lowered blood pressure in all three groups over 24 h.It is suggested that smaller doses of lisinopril should be administered to patients with severe renal failure.     

Elimination kinetics of sulfadiazine in patients with normal and impaired renal function

A linear relationship between the elimination rate constant of sulfadiazine and the endogenous creatinine clearance is demonstrated in 29 patients with normal or with impaired kidney junction. The mean half- life of the drug is 10 hr in patients with normal kidney junction and 22 hr in anuric patients. The value of the relative distribution volume is about 0.36 liter/kg body weight in patients with normal or with impaired kidney function. The renal plasma water clearance of sulfadiazine is 27 ml/min, and the majority of the drug is reabsorbed. The elimination of sulfadiazine during the night is slightly slower than during the day.Supported by Swiss National Research Foundation.     

Pharmacokinetics of cephacetrile in patients with normal or impaired renal function

Summary The pharmacokinetics of cephacetrile, administered as a single i. v. injection of 15 mg/kg, have been determined in 8 patients with normal renal function and in 12 patients with a varying degree of renal impairment. A two-compartment model was used to describe the biphasic decline in serum concentrations and to calculate the amount of antibiotic in the central and peripheral compartments. In patients with normal renal function the following values were obtained for various pharmacokinetic parameters: =3.971 h^–1; =0.343 h^–1; K₁₂=1.745 h^–1; K₂₁=0.763 h^–1; K_el=1.793 h_–1; V_c=8.181; V_p=18.401 and V_dss=26.581. Cephacetrile had some of the highest apparent distribution volumes of all the cephalosporins. Impaired renal function significantly affected , , K₁₂, and K_el. A linear relationship between K_el of cephacetrile and creatinine clearance was demonstrated. The elimination of cephacetrile in anuric patients was about ten times slower than in patients with normal renal function.     

Pharmacokinetics of cefoxitin in patients with normal or impaired renal function

The pharmacokinetics of cefoxitin have been determined after a single i.v. injection of 15 mg/kg body weight in 10 patients with normal renal function and 20 patients with varying degrees of renal impairment. The kinetics of the antibiotic followed an open two-compartment model. In patients with normal renal function the following pharmacokinetic parameters were found: alpha = 8.66 h-1 beta = 1.21 h-1 K12 = 3.47 h-1 K21 = 3.17 h-1 K13 = 3.15 h-1 Vc = 4.24 l. Vp = 4.87 l. Vdss = 9.11 l. In the patients with renal impairment there was a significant decrease in alpha, beta, K12, K21 and K13, and an increase in the apparent volume of distribution. The degree of plasma protein binding in patients with normal renal function was 73.6% and this was diminished in patients with renal impairment. A linear relationship between K13 of cefoxitin and creatinine clearance was demonstrated. The dosage regimen for patients with renal impairment should be adjusted by modifying the dosage interval whilst maintaining the amount administered.