Pharmacokinetics of moxalactam in patients with renal failure and during hemodialysis

The pharmacokinetics of moxalactam were determined in eight patients with end stage renal disease who were undergoing chronic hemodialysis. The mean half-life of moxalactam in the interdialysis period was 19 h, with a range of 9 to 30 h. The mean half-life of moxalactam during dialysis was 4 +/- 0.58 h. Serum levels of 30 +/- 10 micrograms/ml were present 24 h after a 1-g dose in the interdialysis period. A dose of 1 g at the end of each dialysis period in patients undergoing thrice-weekly hemodialysis would provide levels far in excess of the minimal inhibitory levels against Enterobacteriaceae.     

Moxalactam pharmacokinetics during hemodialysis.

To establish dosage recommendations, moxalactam elimination kinetics were studied in six anephric patients during hemodialysis and in four anephric patients during the interdialytic period. After a single 1-g intravenous bolus injection, moxalactam elimination half-life was 18.0 plus or minus 0.6 h with a volume of distribution of 20.2 plus or minus 3.6 liters and a plasma clearance of 12.8 plus or minus 2.0 ml/min in four nondialyzed patients. Moxalactam elimination half-life was decreased to 2.7 plus or minus 0.2 h during hemodialysis in six patients. After 4 h, 48.5% of the dose was recovered in the dialysate. The maintenance dose of moxalactam should be decreased to 15% of a normal dose in patients with creatinine clearances less than 10 ml/min, and 50% of a loading dose should be given after hemodialysis.     

Comparative pharmacokinetics of ceftazidime and moxalactam

The pharmacokinetics of ceftazidime and moxalactam were compared after intravenous and intramuscular administration of single 1-g doses to eight healthy volunteers in a crossover study. The bioavailability of the antibiotics after administration by either route was almost complete. Both drugs had similar areas under the serum curves. Significant differences between ceftazidime and moxalactam were observed with respect to the apparent volume of distribution (18.4 and 24.1 liters, respectively), to the terminal half-life (1.6 versus 2.0 h), and to urinary recovery of the active compound (96 versus 79%). Ceftazidime was almost completely eliminated by renal excretion (greater than 96%), whereas about 20% of the moxalactam was eliminated by nonrenal mechanisms. The concentrations of ceftazidime and moxalactam in serum after a 1-g dose exceeded the concentrations required to inhibit 90% of the Enterobacteriaceae for about 8 and 10 h, respectively. The levels of ceftazidime and moxalactam in serum exceeded the 90% minimal inhibitory concentration of Pseudomonas aeruginosa for about 6 and 1 h, respectively.     

Pharmacokinetics of ampicillin (2.0 grams) and sulbactam (1.0 gram) coadministered to subjects with normal and abnormal renal function and with end-stage renal disease on hemodialysis.

The single-dose pharmacokinetics of intravenously administered ampicillin (2.0 g) and sulbactam (1.0 g) were studied in normal subjects and in patients with various degrees of creatinine clearance (CLCR). Six normal subjects (CLCR, greater than 60 ml/min), six patients with mild renal failure (CLCR, 31 to 60 ml/min), four patients with severe renal failure (CLCR, 7 to 30 ml/min), and four patients requiring maintenance hemodialysis (CLCR, less than 7 ml/min) were studied. The terminal half-lives for ampicillin and sulbactam more than doubled in patients with severe renal failure compared with subjects with normal renal function and mild renal insufficiency. CLCR significantly correlated with ampicillin (r = 0.88) and sulbactam (r = 0.54) total body clearance. Mean steady-state volume of distribution and nonrenal clearance for ampicillin and sulbactam were not affected by renal function. Hemodialysis approximately doubled the ampicillin and sulbactam total body clearance. Mean totals of 34.8 +/- 4.0% of the ampicillin dose and 44.7 +/- 3.2% of the sulbactam dose were removed during a 4-h hemodialysis treatment. A slight rebound in concentrations in serum after hemodialysis was observed for both drugs in all four subjects. In hemodialysis patients, the ampicillin half-life was 17.4 +/- 8.0 h and the sulbactam half-life was 13.4 +/- 7.4 h. The ampicillin and sulbactam half-lives were appreciably altered during the hemodialysis period (means of 2.2 and 2.3 h, respectively). The nearly parallel decrease in total body clearance, with volume of distribution and nonrenal clearance remaining relatively constant, suggests that the same ratio of ampicillin to sulbactam is appropriate regardless of renal function. An adjustment of the ampicillin (2.0 g) and sulbactam (1.0 g) dose to twice daily would be appropriate in patients with a CLCR between 7 and 30 ml/min. Doses should be given every 24 h for those undergoing maintenance hemodialysis. On hemodialysis days, doses should be given after hemodialysis.     

Pharmacokinetics of Cefamandole in the Presence of Renal Failure and in Patients Undergoing Hemodialysis

The pharmacology of cefamandole in seven patients with stable renal insufficiency and in eight patients undergoing hemodialysis was determined. All patients had creatinine clearances less than 5 ml/min. The half-life of cefamandole in those patients with stable chronic renal failure was 7.7 ± 2.2 h. The mean venous level 1 h after intravenous injection of a 1-g dose was 85.3 ± 32.0 μg/ml. The mean venous half-life of cefamandole during hemodialysis was 6.1 h. The venous serum level after 5.5 of hemodialysis was 50.4 ± 20.8 μg/ml. The mean coefficient of extraction was 0.155, and the mean clearance was 34.7 ml/min. The time interval between doses of cefamandole administered intravenously should be lengthened to 24 h in the presence of stable renal failure. No major change in dosage schedule is necessary for patients undergoing dialysis.     

Pharmacokinetics of Netilmicin in the Presence of Normal or Impaired Renal Function

A pharmacokinetic study of netilmicin was conducted in 12 healthy subjects and 24 subjects with chronic renal failure. After intramuscular administrations of 2 and 3 mg of netilmicin per kg in normal subjects, the mean peak serum concentrations were 5.46 and 8.83 μg/ml, respectively. After intravenous infusions of identical doses, the mean maximum serum levels, occurring at the end of the infusion, were 11.79 and 15.75 μg/ml, respectively. The pharmacokinetic data were very similar via the two routes of administration and for the two doses. The elimination half-life was 2.20 h, and 80 to 90% of the injected dose was recovered in urine during the first 24 h. After intramuscular administration of 2 mg/kg in subjects with chronic renal impairment, the elimination half-life increased to 29.48 h, and urinary elimination was inversely related to the degree of impairment. A study was conducted throughout hemodialysis sessions: serum concentrations decreased by 63.3%. The linear relationships between the elimination rate constant and creatinine clearance and the elimination half-life and serum creatinine allowed us to establish dosage schedules according to the degree of renal failure.     

Pharmacokinetics of Cefaclor in Patients with End Stage Renal Disease and During Hemodialysis

A single 1.0-g dose of cefaclor administered to patients with stable end stage renal disease whose creatinine clearances were <5 ml/min produced a mean peak serum concentration of 48.3 ± 19.8 μg/ml. The half-life was 2.3 ± 0.3 h. Hemodialysis shortened the half-life of a similar dose to 1.6 ± 0.3 h. Approximately one-third (340 mg) of the administered drug was recovered in the dialysate. Multiple doses of 500 mg every 6 h between hemodialysis sessions produced effective serum concentrations and no bioassay evidence of drug accumulation.     

Mezlocillin Pharmacokinetics After Single Intravenous Doses to Patients with Varying Degrees of Renal Function

The pharmacokinetics of mezlocillin were examined after single 2- and 4-g intravenous injections to three groups of male patients with creatinine clearances of I ≥ 60, II = 21 to 59, and III ≤ 20 ml min⁻¹ 1.73 m⁻². The decline in serum antibiotic levels was biphasic in all groups, and serum data were interpreted in terms of the pharmacokinetic two-compartment model. The mean elimination half-life of mezlocillin after the 2-g dose was 1.3, 1.5, and 2.3 h in groups I, II, and III, respectively. Equivalent values after the 4-g dose were 1.2, 1.6, and 4.4 h. In three functionally anephric patients the mean serum half-life of mezlocillin was 1.5 h during hemodialysis. Mean antibiotic levels in serum were greater than 10 μg ml⁻¹ for 4 h after the 2- and 4-g doses in group I and 8 h in group II. In group III, levels greater than 10 μg ml⁻¹ were maintained for 6 h after the 2-g dose and over 12 h after the 4-g dose. Mezlocillin distribution characteristics were largely independent of renal function and dose size. The only observable change occurred in the value of V_dss, which was significantly increased to 0.32 with 0.38 liter kg⁻¹ in severe renal impairment, compared to ca. 0.2 liter kg⁻¹ in subjects with normal or slightly impaired renal function. Cumulative 24-h urinary excretion accounted for 50, 40, and 3.2% of the dose in groups I, II, and III, respectively. Urine levels of mezlocillin were uniformly greater than the minimum inhibitory concentration for susceptible organisms for 12 h after dosing in all patients who produced urine. Because of the relatively small increase in the mezlocillin elimination half-life with declining renal function, dose reduction is necessary only in cases of severe renal impairment.     

Clinical pharmacology of moxalactam in patients with malignant disease.

Pharmacological studies of moxalactam were conducted with 37 cancer patients. Intramuscular administration of 500 mg of moxalactam to 10 patients produced a mean peak serum concentration of 12.4 micrograms/ml. The serum terminal-phase half-life was 3.9 h. Intravenous administration of 500 mg of moxalactam over 5 min to the same 10 patients produced a mean serum concentration of 42.0 micrograms/ml at 15 min, which decreased to 3.3 micrograms/ml at 6 h. A dose of 1 g of moxalactam was given in an identical manner to the same 10 patients. The mean serum concentration was 69.7 micrograms/ml at 15 min and 7.4 micrograms/ml at 6 h. The mean proportions of a drug recovered in the urine by 12 h after administration were 59% after the intramuscular dose and 61 and 55% after the single intravenous doses. Multiple-dose intravenous studies were also conducted. The serum terminal-phase half-life varied from 2.0 to 3.2 h. Continuous infusion studies were performed by up to 9 days by using a loading dose of 1 g over 0.5 h, followed by 2 g every 6 h. Serum concentrations were maintained at about 30.0 micrograms/ml during the study period.     

Pharmacokinetics of mezlocillin in patients with kidney impairment: special reference to hemodialysis and dosage adjustments in relation to renal function

The pharmacokinetics of Mezlocillin were determined after the intramuscular injection of a single 1-gram dose in 10 subjects with normal renal function, in 10 patients with stabilized renal impairment and in 5 patients with end-stage renal disease submitted to repeated hemodialysis. In normal subjects, biological half-life, Tb1/2, was equal to 0.9 h; total clearance (Ct) to 449 ml/min/1.73 m2; renal clearance (Cr) to 263 ml/min/1.73 m2.72.2% of the administered dose was excreted in the urine within 12 h. In patients with renal insufficiency and in patients undergoing long-term hemodialysis, the serum concentration decrease was markedly slower. During a 6-hour dialysis session, 62% of the Mezlocillin present in the central compartment at the start of hemodialysis was removed. In the 25 subjects under study, a significant correlation was found between the values of Ke and those of creatinine clearance, Ccr (Ke = 0.1973+0.0046 Ccr). This relation was used to calculate the loading doses, the maintenance doses and the dosage intervals adjusted to the degree of renal impairment, allowing assessment of useful dosage recommendations.     

Pharmacokinetics of moxalactam in subjects with various degrees of renal dysfunction.

We have examined the pharmacokinetics of moxalactam (LY127935) in 36 subjects with various degrees of renal dysfunction. Creatinine clearance (Ccr)/1.73 m2 ranged from zero to 135.8 ml/min. After a 1-g administration of moxalactam intravenously, the volume of distribution was 20.6 /+- 9.5 liters (0.28 liter/kg), and the mean half-life ranged from 3.1 h for subjects with Ccr greater than 65 ml/min to 19.3 h for subjects with Ccr less than 10 ml/min. The moxalactam clearance was closely correlated to Ccr (r = 0.93, P less than 0.0001) and excretion of antibiotic was 73.6 +/- 13% in normal subjects. Renal clearance accounted for 90% of moxalactam clearance in the normal subjects. A dosage schedule for administering moxalactam to patients with various degrees of renal dysfunction is provided.     

Elimination kinetics of ceftizoxime in humans with and without renal insufficiency.

The pharmacokinetics of a single 500-mg intramuscular dose of ceftizoxime were studied in 11 healthy adult volunteers and in 22 patients with various degrees of renal dysfunction. The mean serum half-life of ceftizoxime was 1.44 h in normal subjects and 30.2 h in hemodialysis patients. A significant correlation (P less than 0.001) between the elimination rate constant of ceftizoxime and creatinine clearance was demonstrated. The mean urinary recovery in normal subjects was 75.6% within 6 h of dosage; recovery decreased progressively with reduced renal function.     

Pharmacokinetics of cefotetan in normal subjects and patients with impaired renal function

The elimination kinetics of cefotetan (YM09330), a new parenteral semisynthetic cephamycin derivative, were studied in eight healthy volunteers and 41 patients with renal insufficiency after the administration of a single 500-mg dose intravenously. Concentrations of cefotetan in serum and urine were determined by both bioassay and high-pressure liquid chromatography. The pharmacokinetic parameters for cefotetan were calculated on the basis of a two-compartment open model. Serum concentrations of cefotetan immediately after administration were approximately 180 micrograms/ml in all subjects regardless of function; however, serum concentrations during the beta-phase increased directly with the degree of renal impairment. The mean serum half-life during the beta-phase was 3.0 h in normal subjects as compared with 13.1 h in hemodialysis patients. There was a linear correlation (P less than 0.0001) between the elimination rate constant of cefotetan and creatinine clearance. The mean cumulative urinary recovery of cefotetan in the 24-h urine was 83.3% of the administered dose in normal subjects and decreased with reduced renal function.     

Effect of Renal Failure and Dialysis on the Serum Concentration of the Aminoglycoside Amikacin

Serum and dialysate levels of amikacin were determined at appropriate intervals after a 300-mg intravenous dose as a continuous infusion in six patients with end-stage renal failure undergoing hemodialysis and in three patients on peritoneal dialysis. The mean serum half-life of amikacin was 3.75 h during (or after) hemodialysis and 29 h during (or after) peritoneal dialysis. Although not on hemodialysis in the same six patients, the serum half-life was 28 h. The results indicate that the maintenance dose of amikacin should be markedly decreased in patients with severe renal failure even if they are treated with peritoneal dialysis, and that serial serum antibiotic concentrations are essential to prevent cumulative toxicity of the drug.     

Comparison of steady-state pharmacokinetics of two dosage regimens of vancomycin in normal volunteers.

A pharmacokinetic comparison of the two recommended dosages of vancomycin given as multiple doses has not been previously performed. Eleven adult subjects with normal renal function randomly received 500 mg every 6 h (five doses) and, later, 1,000 mg every 12 h (three doses). Each dose was infused over 1 h, and regimens were separated by 1 week. Compared with the two-compartment fit, a three-compartment fit significantly reduced the residual weighted sums of squares. Accumulation occurred for both regimens after repeated dosing and was independent of dose. At steady state, concentrations in serum at 1 h showed little variation for the 1,000- or the 500-mg dose regimen (33.7 +/- 3.8 versus 22.6 +/- 3.2 micrograms/ml); trough concentrations were 7.9 +/- 1.7 versus 11.2 +/- 2.2 micrograms/ml, respectively. With the 1,000-mg dose, the terminal half-life was 7.7 +/- 1.8 h, steady-state area under the curve for the dose interval was 227 +/- 28.3 micrograms X h/ml, and total body clearance was 86.1 +/- 8.9 ml/min per 1.73 m2. The red-man syndrome occurred in 9 of 11 volunteers who received 1,000-mg doses and in none of those who received 500-mg doses. We concluded that vancomycin disposition in healthy adults with normal renal function is best described by a three-compartment model, there is relatively little variation in vancomycin disposition in normal volunteers, significant accumulation occurs with multiple dosing, it is inappropriate to use the same therapeutic window for both regimens, and the pharmacokinetics of vancomycin justify a 12-h dose interval; however, a 1-g dose is associated with a significantly greater incidence of the red-man syndrome.     

Comparison of cefotaxime and moxalactam pharmacokinetics and tissue levels.

The pharmacokinetics of cefotaxime and moxalactam were compared in six healthy male volunteers aftr the administration of 1-g doses intravenously. Penetration of the compounds into tissue fluid was studied in cantharides-induced blisters. Both serum and tissue fluid levels of moxalactam were higher than those of cefotaxime. The elimination half-life of cefotaxime was 1.2 h, and that of moxalactam was 2.85 h. On the average, 50.5% of cefotaxime and 87.5% of moxalactam were recovered in the urine in 24 h.     

Pharmacokinetics of meropenem (ICI 194,660) and its metabolite (ICI 213,689) in healthy subjects and in patients with renal impairment.

The pharmacokinetics of meropenem (ICI 194,660) and its open-ring metabolite (ICI 213,689) were studied in 6 healthy volunteers and 16 patients with moderate to severe renal impairment after a single intravenous dose of 500 mg given as a 30-min infusion. Concentrations of unchanged meropenem in plasma and urine were measured by both microbiological and high-pressure liquid chromatographic (HPLC) assays. A good correlation was found between the two techniques. Pharmacokinetic parameters of unchanged meropenem were determined by using the HPLC data. The terminal half-life of unchanged meropenem increased in relation to the degree of renal impairment, being 1.2 h in subjects with normal renal function and 10 h in patients with end-stage renal failure. Total body clearance and renal clearance of unchanged meropenem are linearly related to creatinine clearance. The concentrations of the metabolite in plasma, which are very low in healthy subjects, significantly increased in uremic patients. The apparent half-life of ICI 213,689 increased in uremic patients and was about 35 h in patients with severe renal insufficiency. Meropenem and its metabolite are effectively removed by hemodialysis. The dialysis clearance of the unchanged drug was 81 +/- 22 ml/min. Dosage adjustments of meropenem will be necessary in patients with severe renal impairment.     

Pharmacokinetics of cefotiam in patients with impaired renal function and in those undergoing hemodialysis.

The pharmacokinetics of cefotiam were studied after a single intravenous 1.0-g dose to 18 subjects grouped according to their creatinine clearances (CLCR); CLCR was above 75, 75 to 20, and below 20 ml/min per 1.73 m2 in groups 1, 2, and 3, respectively. Cefotiam obeyed two-compartment model kinetics in all three groups. The volume of distribution based on the area under serum concentration-time curve (Varea) was renal function independent, the average value being 0.350 +/- 0.159 liters/kg. The elimination-phase half-life (t1/2 beta) was 0.916 +/- 0.090 h in group 1, 2.03 +/- 1.62 h in group 2, and 7.09 +/- 3.06 h in group 3. Cumulative 24-h urinary excretion accounted for 65 to 93% of the dose in four subjects with CLCRS above 80 ml/min per 1.73 m2 and 19 to 41% in three subjects with CLCRS below 20 ml/min per 1.73 m2. We give recommendations for dosage adjustment in patients with renal insufficiency. The effect of hemodialysis on cefotiam pharmacokinetics was studied in six patients in end-stage renal failure; hemodialysis shortened the average t1/2 beta from 8.02 +/- 4.04 h to 2.74 +/- 2.15 h. We estimated that in a hypothetical anephric patient with a body weight of 60 kg, 6-h hemodialysis would remove 49.7% of the drug present in the body at the start of dialysis.     

Clinical Pharmacology of Ceftriaxone in Patients with Neoplastic Disease

Pharmacological studies of ceftriaxone, a new semisynthetic cephalosporin, were conducted in 35 cancer patients. This antibiotic was administered in a variety of doses and schedules with no observed toxicity. Intramuscular administration of 500 mg of ceftriaxone to seven patients produced mean peak serum concentrations of 32.9 μg/ml 2.0 h after administration. The terminal serum half-life was 10.9 h. Intravenous infusion of 500 mg of ceftriaxone over 5 min to the same group of seven patients produced a mean peak concentration of the drug in serum of 83 μg/ml at the end of administration which decreased to 16.8 μg/ml at 8 h. A dose of 1 g of ceftriaxone given in identical fashion to the same group of seven patients produced mean peak concentrations in serum of 130 μg/ml at the end of administration and 17.3 μg/ml at 12 h. The mean percentages of drug recovered in urine 12 h after single intravenous doses of 500 mg and 1 g were 30 and 20%, respectively. A 1-g dose of ceftriaxone was administered every 8 h to 10 patients, and a 2-g dose was administered every 12 hours to 9 patients. Drug concentrations in serum were measured for each patient after drug administration on day 1, day 3 or 4, and day 7 or 8. The 1-g dose produced an observed mean peak concentration of 154 μg/ml and a mean terminal-phase half-life of 5.6 h on day 3 or 4. The 2-g dose produced a mean peak concentration in serum of 262 μg/ml and a terminal-phase serum half-life of 6.3 h on day 3 or 4. Continuous infusion studies were performed in nine neutropenic patients for up to 8 days by using a loading dose of 1 g over 30 min, followed by 2 g every 8 h. Mean concentrations in serum were maintained at about 135 μg/ml during the infusion period.     

Pharmacokinetics of aztreonam in patients with various degrees of renal dysfunction

We have studied the pharmacokinetics of 1-g intravenous doses of aztreonam in four groups of six volunteers each, distinguished by their creatinine clearances (greater than 80, 30 to 80, 10 to 29, and less than 10 ml/min). Subjects received 1 g of aztreonam intravenously without any complications. Aztreonam serum and urine levels were measured by microbiological methods and by high-pressure liquid chromatography, and unbound serum aztreonam was determined by ultrafiltration. Serum levels were well described by a two-compartment infusion model. From this model we determined steady-state volume of distribution, alpha distribution phase half-life, beta elimination phase half-life, and total clearance of aztreonam. The mean of beta elimination phase half-life ranged from 2 h in normal subjects to 6 h in anephric patients. The total clearance of aztreonam correlated closely with corrected creatinine clearance calculated from serum creatinine, age, and sex (r = 0.97, P less than 0.001) and ranged from a mean value of 107 ml/min in normal subjects to 29 ml/min in functionally anephric patients. Some 75% of aztreonam excretion was renal. Urinary recovery of aztreonam ranged from 58% of the administered dose in normal subjects to 1.4% in uremic patients. Free aztreonam in serum correlated inversely with creatinine clearance (P less than 0.001). A nomogram was developed as a guide for adjustment of aztreonam dosage according to renal function.