Population pharmacokinetics of meropenem during continuous infusion in surgical ICU patients.

Continuous infusion of meropenem is a candidate strategy for optimization of its pharmacokinetic/pharmacodynamic profile. However, plasma concentrations are difficult to predict in critically ill patients. Steady-state concentrations of meropenem were determined prospectively during continuous infusion in 32 surgical ICU patients (aged 21-85 years, body weight 55-125 kg, APACHE II 5-29, measured creatinine clearance 22.7-297 mL/min). Urine was collected for the quantification of renal clearance of meropenem and creatinine. Cystatin C was measured as an additional marker of renal function. Population pharmacokinetic models were developed using NONMEM(®) , which described total meropenem clearance and its relationship with several estimates of renal function (measured creatinine clearance CLCR , Cockcroft-Gault formula CLCG , Hoek formula, 1/plasma creatinine, 1/plasma cystatin C) and other patient characteristics. Any estimate of renal function improved the model performance. The strongest association of clearance was found with CLCR (typical clearance = 11.3 L/h × [1 + 0.00932 × (CLCR - 80 mL/min)]), followed by 1/plasma cystatin C; CLCG was the least predictive covariate. Neither age, weight, nor sex was found to be significant. These models can be used to predict dosing requirements or meropenem concentrations during continuous infusion. The covariate CLCR offers the best predictive performance; if not available, cystatin C may provide a promising alternative to plasma creatinine.

Population pharmacokinetics and pharmacodynamics of meropenem in Japanese pediatric patients.

The aims of this study were to develop a population pharmacokinetic model for meropenem in Japanese pediatric patients, and to use this model to assess the pharmacodynamics of meropenem regimens against common bacterial populations. Pharmacokinetic data were pooled from nine separate studies (229 plasma samples and 61 urine samples from 40 infected children), modeled using the NONMEM program, and used for a pharmacodynamic simulation to estimate the probabilities of attaining the bactericidal target (40% of the time above the MIC for the bacterium). In the final population pharmacokinetic model, body weight (BW, kg) was the most significant covariate: Cl(r) (l/h) = 0.254 x BW, Cl(nr) (l/h) = 3.45, V (c) (l) = 0.272 x BW, Q (l/h) = 1.65, and V (p) (l) = 0.228 x BW, where Cl(r) and Cl(nr) are the renal and non-renal clearances, V (p) and V (c) are the volumes of distribution of the central and peripheral compartments, and Q is the intercompartmental (central-peripheral) clearance. In most typical patients (BW = 10, 20, and 30 kg), the approved regimens of 10-40 mg/kg, three times a day (0.5-h infusions), achieved a target attainment probability of >80% against Escherichia coli, Streptococcus pneumoniae, methicillin-susceptible Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa isolates. The results of this study provide a better understanding of the pharmacokinetics and pharmacodynamics of meropenem in Japanese pediatric patients.

Meropenem pharmacokinetics in the newborn.

We studied meropenem in 23 pre-term (gestational age, 29 to 36 weeks) and 15 full-term (gestational age, 37 to 42 weeks) neonates. Meropenem doses of 10, 20, and 40 mg/kg were administered as single doses (30-min intravenous infusion) on a random basis. Blood was obtained for determining the meropenem concentration nine times. Each child required other antimicrobials for proven/suspected bacterial infections. Samples were assayed by high-performance liquid chromatography analysis. Population pharmacokinetic parameter values were obtained by employing the BigNPAG program. Model building was performed by the likelihood ratio test. The final model included estimated creatinine clearance (CLcr) (Schwartz formula) and weight (Wt) in the calculation of clearance (meropenem clearance = 0.00112 x CLcr + 0.0925 x Wt + 0.156 liter/hr). The overall fit of the model to the data was good (observed = 1.037 x predicted - 0.096; r2 = 0.977). Given the distributions of estimated creatinine clearance and weight between pre-term and full-term neonates, meropenem clearance was substantially higher in the full-term group. A Monte Carlo simulation was performed using the creatinine clearance and weight distributions for pre-term and full-term populations separately, examining 20- and 40-mg/kg doses, 8- and 12-h dosing intervals, and 0.5-h and 4-h infusion times. The 8-h interval produced robust target attainments (both populations). If more resistant organisms were to be treated (MIC of 4 to 8 mg/liter), the 40-mg/kg dose and a prolonged infusion was favored. Treating clinicians need to balance dose choices for optimizing target attainment against potential toxicity. These findings require validation in clinical circumstances.

[The impact of different renal function measuring methods on the dosages of meropenem, piperacillin/tazobactam and cefepime in critically ill patients]. / Impacto de distintos métodos de estimación de la función renal en la dosificación de meropenem, piperacilina/tazobactam y cefepima en pacientes críticos.

OBJECTIVE: Assesment of dosage deviations of three ss-lactam antibiotics eliminated through the kidneys (meropenem, piperacillin/tazobactam and cefepime) by comparison of two prediction formulae, Cockroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) with 24 h urinary creatinine clearance (CrCl(24h)), as a reference method. METHOD: 125 samples of 61 critically ill patients (each one with CG, MDRD y CrCl(24h) values) were classified in one of the five stages of the National Kidney Foundation (NKF) according to CrCl(24h). Dosage discrepancies for each antibiotic based on CG y MDRD were studied in reference to CrCl(24h) by percentage agreement and weighted kappa. At each of the NKF stages, daily dosage differences (Delta=DosisCG-DosisCrCl(24h); Delta=DosisMDRD-DosisCrCl(24h)) and percentage of samples with dosage discrepancies by CG and MDRD in reference to CrCl(24h) were calculated. RESULTS: There were no statistically significant differences between the two prediction formulae in respect to CrCl(24h), achieving good degrees of concordance. Deviation percentages fluctuated between 15.2% and 28% and occurred mainly by underdosing on stages 1 and 2 and by overdosing on stages 4 and 5. CONCLUSIONS: The two renal function prediction formulae can be indistinctly used to optimize the ss-lactam antibiotics dose regimen, CG being the easiest one.

Electrochemical study of imipenem's primary metabolite at the mercury electrode. Voltammetric determination in urine.

Imipenem shows a fast chemical conversion to the more stable imin form (identical to that from biochemical dehydropeptidase degradation) in aqueous solutions that shows a wave at lower cathodic potential than the imipenem one. The aim of this work is the study of the electrochemical behaviour of the primary metabolite of imipenem (M1) and the proposal of electrochemical methods for the determination of M1 in human urine samples. Electrochemical studies were realized in phosphate buffer solutions over pH range 2.0-8.0 using differential pulse polarography, dc-tast polarography, cyclic voltammetry and linear sweep voltammetry (staircase). In acidic media, a non-reversible diffusion-controlled reduction involving two electrons and two protons occurs and the mechanism for the reduction was suggested. A differential pulse polarographic method for the determination of M1 in the concentration range 10(-6) to 10(-4)M with a detection limit of 4.5 x 10(-7)M was proposed. Also, a method based on controlled adsorptive pre-concentration of M1 on the hanging mercury drop electrode (HMDE) followed by linear sweep voltammetry allows its determination in the concentration range 2 x 10(-9) to 4 x 10(-8)M with a detection limit of 1.05 x 10(-9)M. The proposed methods have been used for the direct determination of M1 in spiked human urine and real human-derived urine with good results and should be appropriate for monitoring purposes.

Plasma pharmacokinetics and urine concentrations of meropenem in ewes.

The pharmacokinetics of meropenem was studied in five ewes after single i.v. and i.m. dose of 20 mg/kg bw. Meropenem concentrations in plasma and urine were determined using microbiological assay method. A two-compartment open model was best described the decrease of meropenem concentration in plasma after an i.v. injection. The drug was rapidly eliminated with a half-life of elimination (t1/2beta) of 0.39 +/- 0.30 h. Meropenem showed a small steady-state volume of distribution [Vd(ss)] 0.055 +/- 0.09 L/kg. Following i.m. injection, meropenem was rapidly absorbed with a t1/2ab of 0.25 +/- 0.04 h. The peak plasma concentration (Cmax) was 48.79 +/- 8.83 microg/mL was attained after 0.57 +/- 0.13 h (tmax). The elimination half-life (t1/2el) of meropenem was 0.71 +/- 0.12 h and the mean residence time (MRT) was 1.38 +/- 0.26 h. The systemic bioavailability (F) after i.m. injection was 112.67 +/- 10.13%. In vitro protein-binding percentage of meropenem in ewe's plasma was 42.80%. The mean urinary recoveries of meropenem over 24 h were 83% and 91% of the administered dose after i.v. and i.m. injections respectively. Thus, meropenem is likely to be efficacious in the eradication of many urinary tract pathogens in sheep.

Population pharmacokinetics of arbekacin, vancomycin, and panipenem in neonates.

Immature renal function in neonates requires antibiotic dosage adjustment. Population pharmacokinetic studies were performed to determine the optimal dosage regimens for three types of antibiotics: an aminoglycoside, arbekacin; a glycopeptide, vancomycin; and a carbapenem, panipenem. Eighty-three neonates received arbekacin (n = 41), vancomycin (n = 19), or panipenem (n = 23). The postconceptional ages (PCAs) were 24.1 to 48.4 weeks, and the body weights (BWs) ranged from 458 to 5,200 g. A one-compartment open model with first-order elimination was applied and evaluated with a nonlinear mixed-effect model for population pharmacokinetic analysis. In the fitting process, the fixed effects significantly related to clearance (CL) were PCA, postnatal age, gestational age, BW, and serum creatinine level; and the fixed effect significantly related to the volume of distribution (V) was BW. The final formulas for the population pharmacokinetic parameters are as follows: CL(arbekacin) = 0.0238 x BW/serum creatinine level for PCAs of <33 weeks and CL(arbekacin) = 0.0367 x BW/serum creatinine level for PCAs of > or = 33 weeks, V(arbekacin) = 0.54 liters/kg, CL(vancomycin) = 0.0250 x BW/serum creatinine level for PCAs of <34 weeks and CL(vancomycin) = 0.0323 x BW/serum creatinine level for PCAs of > or = 34 weeks, V(vancomycin) = 0.66 liters/kg, CL(panipenem) = 0.0832 for PCAs of <33 weeks and CL(panipenem) = 0.179 x BW for PCAs of > or = 33 weeks, and V(panipenem) = 0.53 liters/kg. When the CL of each drug was evaluated by the nonlinear mixed-effect model, we found that the mean CL for subjects with PCAs of <33 to 34 weeks was significantly smaller than those with PCAs of > or = 33 to 34 weeks, and CL showed an exponential increase with PCA. Many antibiotics are excreted by glomerular filtration, and maturation of glomerular filtration is the most important factor for estimation of antibiotic clearance. Clinicians should consider PCA, serum creatinine level, BW, and chemical features when determining the initial antibiotic dosing regimen for neonates.

Plasma pharmacokinetics and tissue fluid concentrations of meropenem after intravenous and subcutaneous administration in dogs.

OBJECTIVE: To estimate pharmacokinetic variables and measure tissue fluid concentrations of meropenem after IV and SC administration in dogs. ANIMALS: 6 healthy adult dogs. PROCEDURE: Dogs were administered a single dose of meropenem (20 mg/kg) IV and SC in a crossover design. To characterize the distribution of meropenem in dogs and to evaluate a unique tissue fluid collection method, an in vivo ultrafiltration device was used to collect interstitial fluid. Plasma, tissue fluid, and urine samples were analyzed by use of high-performance liquid chromatography. Protein binding was determined by use of an ultrafiltration device. RESULTS: Plasma data were analyzed by compartmental and noncompartmental pharmacokinetic methods. Mean +/- SD values for half-life, volume of distribution, and clearance after IV administration for plasma samples were 0.67 +/- 0.07 hours, 0.372 +/- 0.053 L/kg, and 6.53 +/- 1.51 mL/min/kg, respectively, and half-life for tissue fluid samples was 1.15 +/- 0.57 hours. Half-life after SC administration was 0.98 +/- 0.21 and 1.31 +/- 0.54 hours for plasma and tissue fluid, respectively. Protein binding was 11.87%, and bioavailability after SC administration was 84%. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of our data revealed that tissue fluid and plasma (unbound fraction) concentrations were similar. Because of the kinetic similarity of meropenem in the extravascular and vascular spaces, tissue fluid concentrations can be predicted from plasma concentrations. We concluded that a dosage of 8 mg/kg, SC, every 12 hours would achieve adequate tissue fluid and urine concentrations for susceptible bacteria with a minimum inhibitory concentration of 0.12 microg/mL.

A rapid, sensitive high performance liquid chromatographic method for the determination of meropenem in pharmaceutical dosage form, human serum and urine.

A new, simple, precise and rapid high performance liquid chromatographic method was developed for the determination of meropenem in human serum, urine and pharmaceutical dosage forms. Chromatography was carried out on an LC(18) column using a mixture of 15 mM KH(2)PO(4):acetonitrile:methanol (84:12:4; v/v/v), adjusted to pH 2.8 with H(3)PO(4). The proposed method was conducted using a reversed-phase technique, UV monitoring at 307.6 nm and cefepime as an internal standard. The retention times were 5.98 and 7.47 min for cefepime and meropenem, respectively. The detector response was linear over the concentration range of 50-10,000 ng/mL. The detection limit of the procedure was found to be 22 ng/mL. The detection limit for meropenem in human plasma was 108.4 ng/mL and the corresponding value in human urine was 179.3 ng/mL. No interference from endogenous substances in human serum, urine and pharmaceutical preparation was observed. The proposed method is sufficiently sensitive for determination of the concentrations of meropenem and may have clinical application for its monitoring in patients receiving the drug.

Capillary zone electrophoresis determination of meropenem in biological media using a high sensitivity cell.

A capillary electrophoresis method with a high sensitivity cell (Z-cell) has been developed for the determination of meropenem in aqueous solution and in biological media (urine, plasma). Water samples were analysed using two calibration curves of meropenem with standard capillary and a capillary with a high sensitivity cell. In urine, the samples were only diluted in buffer and were injected without any further sample preparation. For the analysis of plasma samples, a calibration curve was utilized covering the meropenem concentration range of 0.5-200 microg/ml. The detection limit and the relative standard deviation of the migration times and of the peak areas were determined.

Pharmacokinetics and safety of a new parenteral carbapenem antibiotic, biapenem (L-627), in elderly subjects.

The pharmacokinetics and tolerability of a new parenteral carbapenem antibiotic, biapenem (L-627), were studied in healthy elderly volunteers aged 65 to 74 years (71.6 +/- 2.7 years [mean +/- standard deviation], n = 5; group B) and > or = 75 years (77.8 +/- 1.9 years, n = 5; group C), following single intravenous doses (300 and 600 mg), and compared with those of healthy young male volunteers aged 20 to 29 years (23.0 +/- 3.5 years, n = 5; group A). The agent was well tolerated in all three age groups. Serial blood and urine samples were analyzed for biapenem to obtain key pharmacokinetic parameters by both two-compartment model-dependent and -independent methods. The maximum plasma concentration and area under plasma concentration-versus-time curve (AUC) increased in proportion to the dose in all three groups. Statistically significant age-related effects for AUC, total body clearance, and renal clearance (CLR) were found, while elimination half-life (t1/2 beta) and percent cumulative recovery from urine of unchanged drug (% UR) remained unaltered (t1/2 beta, 1.51 +/- 0.42 [300 mg] and 2.19 +/- 0.64 [600 mg] h [group A], 1.82 +/- 1.14 and 1.45 +/- 0.36 h [group B], and 1.75 +/- 0.23 and 1.59 +/- 0.18 h [group C]; % UR, 52.6% +/- 3.0% [300 mg] and 53.1% +/- 5.1% [600 mg] [group A], 46.7% +/- 7.4% and 53.0% +/- 4.8% [group B], and 50.1% +/- 5.2% and 47.1% +/- 7.6% [group C]). A significant linear correlation was observed between the CLR of biapenem and creatinine clearance at the dose of 300 mg but not at 600 mg. The steady-state volume of distribution tended to be decreased with age, although not significantly. Therefore, the age-related changes in parameters of biapenem described above were attributable to the combination of decreased lean body mass and lowered renal function of the elderly subjects. However, the magnitude of those changes does not necessitate dosage adjustment in elderly patients with normal renal function for their age.

[Meropenem: pharmacologic advantages of clinical interest]. / Meropenem: ventajas farmacológicas de interés clínico.

The pharmacokinetic profile of meropenem is similar to that of imipenem/cilastatin. It differs in resistance to hydrolysis by the methaloenzyme, dehydropeptidase I, and therefore does not require the combination of cilastatin, being administered alone. Similar to other beta-lactamic drugs, it is mainly distributed in the extravascular space (apparent Vd, 21 I) with an half life of elimination of approximately one hour. A low proportion binds to plasma proteins (< 20%). The tissue concentrations are maintained for prolonged periods at values greater than the MIC of most pathogens. In LCR and aqueous humor it has limited penetration. Nonetheless, the levels achieved in patients with meningitis (40 mg/kg/8 h) range between 0.9 and 6.5 micrograms/ml, greater than the MIC of most pathogens associated with this disease. The renal clearance of meropenem surpasses that of creatinine, thereby indicating excretion by glomerular filtration and tubular secretion. The doses in patients with renal insufficiency should be reduced according to creatinine clearance. Modification of the dosage is not necessary in patients with hepatic failure. Administered at a doses of 1 g/8 hours meropenem presented a value of (AUICo infinity) 60-90 micrograms/h/ml. The (AUIC)24 = 125 ensures that the serum concentrations are maintained above 3 micrograms/ml during a period greater than 80% of the dosage interval.

Clinical pharmacokinetics of meropenem after the first and tenth intramuscular administration.

We investigated the pharmacokinetics of meropenem after the first and tenth i.m. administration in patients with respiratory tract infections. Ten patients (mean age 63.8 +/- 5.2 years) received meropenem 500 mg tds for at least ten doses, and plasma and urine antibiotic concentrations were determined by microbiological assay. After the first injection a mean peak plasma concentration of 7.93 +/- 1.29 mg/L was observed at 1 h. Trough levels at 8 h (0.29 +/- 0.16 mg/L) were detectable in five of ten treated patients. The mean terminal half-life was 1.08 +/- 0.2 h with an area under the curve (AUC) value of 23.8 +/- 4.59 mg/L.h, and a cumulative urinary recovery at 8 h of 48.43 +/- 3.12%. There was no evidence of change in the pharmacokinetics of meropenem after repeated i.m. administration, though the mean peak plasma concentration and AUC value were slightly increased. The accumulation ratio (assessed using AUC values) was 1.18 +/- 0.19 after multiple doses and was considered to be of little kinetic and clinical importance. Moreover, many of the trough concentrations of meropenem were below the limit of detection of the assay. After i.m. administration meropenem concentrations exceeded 0.5 mg/L for longer than previously described following i.v. infusion. No adverse events were reported.

[Influence of urine pH and cations on antimicrobial activities of penems].

We compared the antimicrobial activities of penems in human urine with those in Mueller-Hinton broth in order to clarify the usefulness of penems for urinary tract infections. Furthermore, we also investigated the influence of urine components, such as pH, magnesium concentration and calcium concentration, on the antimicrobial activities of penems. Three penems, i.e., imipenem, panipenem and meropenem were employed. And two bacterial strains, i.e., Escherichia coli NIHJ JC-2 and Pseudomonas aeruginosa 18s, were tested. There was no significant difference in MBCs between human urine and Mueller-Hinton broth against E. coli. However, MBCs of penems in human urine was lower than those in Mueller-Hinton broth against P. aeruginosa. On the other hand, MBCs of penems against these two strains were low when urine pH was high or urine calcium concentration was low. No influence of urine magnesium concentration on MBCs of penems was seen. From these results, it was suggested that we should measure the antimicrobial activities of penems not only in Mueller-Hinton broth, but also in human urine, when we administer penems to patients with urinary tract infections. And we should foresee the clinical effects of penems against urinary tract infections paying attention to urine pH of the patients.

Pharmacokinetics of meropenem in patients with various degrees of renal function, including patients with end-stage renal disease.

The pharmacokinetics of meropenem were studied after intravenous infusion in 13 patients grouped according to the impairment of their renal function. Creatinine clearance (CLCR) was greater than 50, 50 to 30, and less than 30 ml/min in groups I, II, and III, respectively. Two other groups, groups IV and V, each comprising four patients with end-stage renal disease (CLCR, < 5 ml/min), were also studied, the former on days off of hemodialysis and the latter on days of hemodialysis. The elimination half-lives of meropenem were 1.54 +/- 0.70 h in group I patients, 3.36 +/- 1.02 h in group II patients, and 5.00 +/- 1.05 h in group III patients. Cumulative urinary excretion accounted for 48.5% of the dose in group I patients and decreased progressively with a decline in renal function. Hemodialysis shortened the elimination half-life of meropenem from 7.0 h to 2.9 h. H-4295, the main metabolite of meropenem, had a peak level in plasma of 0.5 to 1.0 h in patients with renal failure. The level of H-4295 decreased with hemodialysis. The dosing interval of meropenem should be prolonged in a regular proportion to the decline in CLCR (12 h in group II patients and 24 h in group III patients). In patients receiving hemodialysis, dosing after each hemodialysis session is recommended.

Pharmacokinetics of meropenem in subjects with renal insufficiency.

The pharmacokinetics of IV meropenem (500 mg over 30 min) has been studied in 6 healthy volunteers and 26 patients with various degrees of renal impairment. Blood samples were taken at different times over 24 h in healthy subjects and 36 to 48 h in uraemic patients, and four or five urine samples were collected over 24 or 48 h. Meropenem concentrations in plasma and urine were measured by a microbiological assay. The mean peak plasma concentration of meropenem ranged from 28 to 40 micrograms.ml-1 and was not affected by the degree of renal impairment. The terminal half-life of meropenem was approximately 1 h in subjects with normal kidney function and it was proportionately increased as renal function decreased. A significant linear relationship between total body clearance and creatinine clearance as well as between renal clearance and creatinine clearance was observed. The mean apparent volume of distribution at steady state was not significantly altered in uraemic patients. The mean cumulative urinary recovery of meropenem in healthy volunteers was 77% of the administered dose and it was significantly decreased in patients with renal impairment. Haemodialysis shortened the elimination half-life, from 9.7 h during the predialysis period to 1.4 h during the dialysis period. The dose of meropenem should be reduced in relation to the decrease in creatinine clearance.

Pharmacokinetics of meropenem and its metabolite ICI 213,689 in healthy subjects with known renal metabolism of imipenem.

Six healthy male subjects who had received imipenem without cilastatin in previous studies, were given 500 mg meropenem as single 30 min intravenous infusions. Plasma and urine samples were collected for 12 h and meropenem and its metabolite were assayed by HPLC and RIA, respectively. The mean plasma half-life of meropenem was 0.8 h, mean plasma clearance 277 ml/min and the mean volume of distribution 20.4 l. The metabolite reached mean peak plasma concentrations of 1.5 mg/l. Renal clearance of meropenem averaged 200 ml/min. The mean urinary recovery of the metabolite was 20% and of unchanged drug 72% of the dose given. The recovery of meropenem ranged from 62.2% to 78.2% and was correlated to the urinary recovery of imipenem when given without cilastatin to the same subjects in previous studies (range 15.2-32.2%, rank correlation coefficient = 0.934). The results indicate that meropenem is much less susceptible to renal metabolism than imipenem. The inter-subject variability observed with meropenem correlates with the extent of urinary recovery of imipenem observed in previous studies with imipenem alone, indicating some susceptibility of meropenem to renal dehydropeptidase-I.

The pharmacokinetics of meropenem in volunteers.

Two human volunteer studies were performed with meropenem: a dose proportionality study of 0.25, 0.5 and 1.0 g and a probenecid interaction study. Six volunteers took part in each study. Meropenem was generally well tolerated: One volunteer was withdrawn from the dose proportionality study because of looseness of stool and abdominal pain after a dose of 1.0 g. The plasma concentrations of meropenem were linearly related to dose. The half-life of meropenem was approximately 1 h and the urinary recovery of unchanged drug was 79%. In the presence of probenecid the plasma half-life of meropenem was increased by 33% but the urinary recovery was unaffected.

Pharmacokinetics of imipenem and cilastatin after their simultaneous administration to the elderly.

The pharmacokinetics of imipenem and cilastatin were studied in a group of six healthy elderly male volunteers following the combined intravenous administration of 500 mg imipenem and 500 mg cilastatin sodium as either single or multiple (6 hourly for 6 days) 20 min constant-rate infusions. The pharmacokinetics of both imipenem and cilastatin in the elderly were similar to those of young individuals with mild renal failure (Verpooten et al., 1984). There was no change in the pharmacokinetics of either species with time following multiple-dosing. Correlations existed between total clearance and the glomerular filtration-rate (51Cr-EDTA) for both imipenem and cilastatin.

Pharmacokinetics and tolerance after repeated doses of imipenem/cilastatin in patients with severe renal failure.

The pharmacokinetics of imipenem and cilastatin after repeated doses have been studied in six patients with severe renal impairment (mean creatinine clearance 10.4 ml/min/1.73 m2). The patients received nine iv injections of imipenem/cilastatin sodium (500/500 mg) at 12-hour intervals. The imipenem plasma concentration-time profile and the pharmacokinetic parameters on day 5 were similar in all respects to those on day 1. Therapeutic plasma levels of imipenem (greater than or equal to 4 mg/l) were maintained for 8-10 h after administration. Most pharmacokinetic parameters of cilastatin were similar on both days. However, the area under the plasma concentration curve (AUC) was significantly increased on day 5, as a result of some accumulation, but the trough levels stabilized after the third injection. Twice daily administration of imipenem/cilastatin 500/500 mg was felt to be a well tolerated and optimal dose regimen in patients with severe renal failure.