Pharmacokinetics of intramuscularly administered ertapenem

Ertapenem (INVANZ) is a new once-a-day parental beta-lactam antimicrobial agent that has been shown to be highly effective as a single agent for treatment of various community-acquired and mixed infections. The plasma pharmacokinetics of a 1-g intramuscular (i.m.) dose was compared with those of a 1-g intravenous (i.v.) dose infused over 30 min, the recommended rate of i.v. infusion for comparison, and over 120 min, which more closely mimicked the time course for absorption of the i.m. form. In a three-period crossover study (Part A), 26 healthy subjects received single doses of ertapenem administered i.m., i.v. infused over 30 min, and i.v. infused over 120 min. Blood for ertapenem analysis was collected over 24 h postdose for each treatment. In Part B, these fasted subjects received a 1-g i.m. dose of ertapenem once daily for 7 days. Following a 1-g i.m. dose and a 1-g i.v. dose infused over 120 min, the geometric mean area under the concentration curve from hour 0 to infinity (AUC(0- infinity )) was 541.8 micro g. hr/ml following i.m. administration and 591.4 micro g. hr/ml following a 120-min infusion; the geometric mean ratio was 0.92 with a 90% confidence interval of 0.88 to 0.95. The geometric mean AUC(0- infinity ) was nearly identical when 1-g doses were infused over 30 or 120 min. Although the maximum concentration of drug in serum was somewhat lower following i.m. administration than following i.v. administration, the shape of the plasma concentration profiles was roughly comparable at later time points. Ertapenem did not accumulate after multiple 1-g i.m. daily doses over 7 days. The geometric mean ratio for AUC(0-24) (day 7/day 1) was 0.98 with a 90% confidence interval of 0.94 to 1.02. Thus, the relative bioavailability of the 1-g i.m. dose was 92%. Ertapenem does not accumulate following multiple daily 1-g i.m. doses over 7 days.     

Pharmacokinetics of total and unbound ertapenem in healthy elderly subjects

Ertapenem is a new once-a-day parenteral carbapenem antimicrobial agent. The pharmacokinetics of unbound and total concentrations of ertapenem in plasma were investigated in elderly subjects and compared with historical data from young adults. In a single- and multiple-dose study, healthy elderly males and females (n = 14) 65 years old or older were given a 1-g intravenous (i.v.) dose once daily for 7 days. Plasma and urine samples collected for 24 h on days 1 and 7 following administration of the 1-g doses were analyzed by reversed-phase high-performance liquid chromatography. Areas under the concentration-time curve from 0 h to infinity (AUC(0- infinity )) for elderly females and males were similar following administration of 1-g single i.v. doses, and thus, the genders were pooled in subsequent analyses. Concentrations in plasma and the half-life of ertapenem were generally higher and longer, respectively, in elderly subjects than in young adults. The mean AUC(0- infinity ) of total ertapenem in the elderly was 39% higher than that in young subjects following administration of a 1-g dose. The differences were slightly greater for the mean AUC(0- infinity ) of unbound ertapenem (71%). The unbound fraction of ertapenem in elderly subjects ( approximately 5 to 11%) was generally greater than that in young adults ( approximately 5 to 8%). As in young adults, ertapenem did not accumulate upon multiple dosing in the elderly. The pharmacokinetics of ertapenem in elderly subjects, while slightly different from those in young adults, do not require a dosage adjustment for elderly patients.     

Dose-dependent pharmacokinetics of itraconazole after intravenous or oral administration to rats: intestinal first-pass effect

The dose-dependent pharmacokinetics of itraconazole after intravenous (10, 20, or 30 mg/kg) and oral (10, 30, or 50 mg/kg) administration and the first-pass effects of itraconazole after intravenous, intraportal, intragastric, and intraduodenal administration at a dose of 10 mg/kg were evaluated in rats. After intravenous administration at a dose of 30 mg/kg, the area under the plasma concentration-time curve from time zero to infinity (AUC(0- infinity )) was significantly greater than those at 10 and 20 mg/kg (1,090, 1,270, and 1,760 micro g. min/ml for 10, 20, and 30 mg/kg, dose-normalized at 10 mg/kg). After oral administration, the AUC(0- infinity ) was significantly different for three oral doses (380, 687, and 934 micro g. min/ml for 10, 30, and 50 mg/kg, respectively, dose-normalized at 10 mg/kg). The extent of absolute oral bioavailability (F) was 34.9% after an oral dose at 10 mg/kg. The AUC(0- infinity ) (or AUC(0-8 h)) values were comparable between intravenous and intraportal administration and between intragastric and intraduodenal administration, suggesting that the hepatic and gastric first-pass effects were almost negligible in rats. However, the AUC(0-8 h) values after intraduodenal and intragastric administration were significantly smaller than that after intraportal administration, approximately 30%, suggesting that the intestinal first-pass effect was approximately 70% of that of an oral dose of 10 mg/kg. The low F after oral administration of itraconazole at a dose of 10 mg/kg could be mainly due to the considerable intestinal first-pass effect.     

Penetration of ertapenem into skeletal muscle and subcutaneous adipose tissue in healthy volunteers measured by in vivo microdialysis

OBJECTIVES: Ertapenem is FDA approved for the treatment of skin and skin-structure infections (SSSI), but its in vivo penetration into the interstitial space of soft tissues is unknown. The present microdialysis study was conducted to measure free, protein-unbound ertapenem concentrations in muscle and subcutaneous tissue. Volunteers and methods: In a single-centre, prospective, open-label study six healthy volunteers (three females, 22-37 years) were treated with 1 g ertapenem given as a single intravenous dose. Microdialysis and plasma samples were collected before and at different time points up to 12 h after medication. Drug concentrations were determined by a validated LC-MS-MS method. RESULTS: No serious or microdialysis-associated adverse events were observed. Ertapenem concentrations in plasma reached a maximum (C(max)) of 103.3 +/- 26.3 mg/L, a terminal elimination half-life (t(1/2)) of 3.8 +/- 0.6 h and an AUC(0-infinity) of 359.7 +/- 66.5 mg.h/L. Mean peak concentrations of free, protein-unbound ertapenem in interstitial space fluid of skeletal muscle and subcutaneous adipose tissue were much lower (C(max) = 6.7 +/- 4.1 and 4.0 +/- 1.6 mg/L, respectively). This degree of tissue distribution is consistent with high concentration-dependent plasma protein binding of ertapenem (84-96%). AUC(0-infinity) values for both muscle and adipose tissue were lower as well (39.7 +/- 24.8 and 18.6 +/- 4.6 mg.h/L). However, unbound interstitial fluid concentrations exceeded MIC(90) values for the important SSSI pathogens for 7 (subcutis) and 10 h (muscle) after dosing. CONCLUSIONS: These results support the previously observed clinical efficacy of ertapenem in the treatment of SSSI.     

Ertapenem: a Group 1 carbapenem with distinct antibacterial and pharmacological properties

Ertapenem, a Group 1 carbapenem, is the most recent beta-lactam antibiotic to enter clinical practice in the USA and Europe. While structurally a carbapenem, the overall molecular structure of ertapenem has been modified to focus its antibacterial spectrum on important community-acquired aerobic and anaerobic pathogens, and to increase its plasma half-life, permitting once-a-day dosing for this parenteral antibiotic. A number of chemical features are responsible for the unique properties of ertapenem. The inclusion of a trans-1-hydroxyethyl group in the structure of ertapenem enables the drug to maintain antibacterial efficacy against the vast majority of beta-lactamase-producing organisms. A critical 1beta-methyl substituent shields the beta-lactam carbonyl group and serves to reduce dehydropeptidase (DHP)-1 catalysed hydrolysis of the beta-lactam, enabling ertapenem to be administered without a DHP-1 inhibitor. A meta-substituted benzoic acid substituent increases the molecular weight and lipophilicity of the molecule, and the carboxylic acid moiety, ionized at physiological pH, results in ertapenem having a net negative charge. As a result, ertapenem is highly protein bound and has an extended half-life, permitting a once-a-day treatment regimen.     

Pharmacokinetics of an everninomicin (SCH 27899) in mice, rats, rabbits, and cynomolgus monkeys following intravenous administration

The pharmacokinetics of SCH 27899, a novel oligosaccharide compound of the everninomicin class with excellent activity against gram-positive strains, was studied with mice, rats, rabbits, and cynomolgus monkeys following intravenous administration as SCH 27899-N-methylglucamine-hydroxypropyl beta-cyclodextrin. Concentrations of SCH 27899 in mouse serum, rat plasma, and rabbit serum were determined by a high-pressure liquid chromatography method on a poly(styrene-divinyl benzene) column, and those in monkey plasma were determined by a paired-ion chromatographic method. Plasma and serum concentrations of SCH 27899 exhibited a biexponential decline in all species following intravenous administration. The half-lives at beta phase were 3.0 to 7.9 h in mice, rats, and rabbits and 24 h in cynomolgus monkeys. There was a linear relationship between the area under the curve extrapolated to infinity [AUC(I)] in mice and dose. Rabbits also exhibited dose proportionality in AUC(I). However, in rats, increasing the dose from 3 to 60 mg/kg of body weight resulted in a 49-fold increase in AUC(I). When the species was changed from mouse to rat, rabbit, or cynomolgus monkey, AUC(I) increased, whereas clearance (CL) decreased. It was concluded that the pharmacokinetics of SCH 27899 in animals varied with species; CL was the highest in mice and rats, followed by rabbits and cynomolgus monkeys.     

Ertapenem in critically ill patients with early-onset ventilator-associated pneumonia: pharmacokinetics with special consideration of free-drug concentration

OBJECTIVES: Most information about pharmacokinetics of antimicrobial agents is obtained from studies in healthy volunteers. However, antibiotics are therapeutically used in infected patients with very different pharmacokinetic properties compared with healthy individuals. PATIENTS AND METHODS: In a single-centre, prospective, open-label study, 17 adult critically ill patients with early-onset ventilator-associated pneumonia (VAP) were treated with 1 g of ertapenem infusion once a day. Blood and urine samples were collected before and at different time-points up to 24 h after medication on day 1. Concentrations of ertapenem in plasma were determined with a validated HPLC method. Free-drug concentrations were estimated using a two-class binding site equation. RESULTS: The overall clinical success rate of the assessable cases was 66.7% (12/16). Pharmacokinetic parameters of ertapenem in our critically ill patients were clearly different when compared to those reported in the literature for healthy volunteers. The enhanced V(z) (17 vs. 8 L) and CL(TOT) (43 vs. 20 mL/min) with resulting lower C(max) (90 vs. 253 mg/L) and AUC(0-infinity) (418 vs. 817 mg x h/L) values were mainly related to hypoalbuminaemia (range 9.2-25.6 g/L) in our patient population. A population pharmacokinetic analysis using the NONMEM program indicated creatinine clearance as a significant covariate for explaining the between-subject variability of ertapenem in the patient population. Estimated free plasma concentrations of ertapenem exceeded a MIC(90) of 2 mg/L only for 6 h (25%) after infusion. CONCLUSIONS: For an adequate dose adjustment of highly protein-bound drugs like ertapenem, knowledge of actual albumin concentrations is necessary. A shortening of the dosage interval or continuous infusion of ertapenem should be considered to ensure optimal free concentrations in critically ill patients with severe hypoalbuminaemia and normal renal function.     

Tissue penetration by ertapenem,a parenteral carbapenem administered once daily,in suction-induced skin blister fluid in healthy young volunteers

The penetration of 1 g of intravenous ertapenem once daily for 3 days in suction-induced skin blisters was evaluated. Ten forearm blisters were formed (n = 12) 12 h prior to the last dose. Concentrations of ertapenem in blister fluid exceeded 4 micro g/ml (the MIC at which 90% of the isolates tested are eliminated) for the entire dosing interval. The area under the concentration-time curve for 0 to 24 h ratio of blister fluid to plasma was 61% (90% confidence interval, 56, 65%) suggesting good blister penetration.     

Pharmacodynamic activity of ertapenem versus penicillin-susceptible and penicillin-non-susceptible Streptococcus pneumoniae using an in vitro model

BACKGROUND: Ertapenem is a novel carbapenem with activity against both penicillin-susceptible (MIC < or = 0.06 mg/L) and penicillin-non-susceptible (MIC > or = 0.12 mg/L) Streptococcus pneumoniae. This study assessed the pharmacodynamic activity of ertapenem against penicillin-susceptible and penicillin-non-susceptible S. pneumoniae using an in vitro pharmacodynamic model. METHODS: Fifteen S. pneumoniae strains including 3 penicillin-susceptible and 12 penicillin-non-susceptible [4 penicillin-intermediate (MIC 0.12-1 mg/L) and 8 penicillin-resistant (MIC > or = 2 mg/L); with different resistance phenotypes including erythromycin-resistant (MIC > or = 1 mg/L), ciprofloxacin-resistant (MIC > or = 4 mg/L) and doxycycline-resistant (MIC > or = 8 mg/L)] were studied. The in vitro pharmacodynamic model was inoculated with 1 x 10(6) cfu/mL and ertapenem was dosed once daily at 0 and 24 h to simulate f (free) Cmax and t(1/2) obtained after a standard 1 g intravenous once daily dose in healthy volunteers (fCmax 15 mg/L, t(1/2) 4 h). Sampling was performed for 48 h to assess viable growth. RESULTS: Ertapenem T(> MIC) > or = 80% (ertapenem MICs < or = 0.5 mg/L) resulted in bactericidal (> or = 3 log10 killing) activity at 12, 24 and 48 h with complete eradication of penicillin-susceptible and penicillin-non-susceptible S. pneumoniae from the model with no regrowth over the 48 h study period. Ertapenem T(> MIC) < or = 63% (ertapenem MIC > or = 1 mg/L) resulted in bactericidal activity at 12 h with regrowth at 24 and 48 h. The observed MICs for S. pneumoniae of ertapenem studied in the in vitro model did not change during the 48 h period, even for strains where regrowth occurred. CONCLUSIONS: Ertapenem is bactericidal against both penicillin-susceptible and penicillin-non-susceptible S. pneumoniae (ertapenem MICs < or = 0.5 mg/L) when simulating free drug after 1 g intravenous once daily dosing.     

ABT-773: pharmacokinetics and interactions with ranitidine and sucralfate

We assessed the pharmacokinetics and interaction of ABT-773 in 12 volunteers receiving ABT-773 alone or concomitantly with ranitidine or sucralfate. Data for 150 mg of ABT-773 were as follows: the maximum concentration of the drug in plasma (C(max)) was 318 ng/ml, its half-life was 5.66 h, and its area under the plasma concentration-time curve from 0 h to infinity (AUC(0- infinity )) was 1,662 ng. h/ml. Coadministration of ranitidine, reduced the C(max) (-25.7%) and AUC(0- infinity ) (-15.8%) significantly. Sucralfate had no impact on the bioavailability of ABT-773.     

Compartmental pharmacokinetics of the antifungal echinocandin caspofungin (MK-0991) in rabbits

The pharmacokinetics of the antifungal echinocandin-lipopeptide caspofungin (MK-0991) in plasma were studied in groups of three healthy rabbits after single and multiple daily intravenous administration of doses of 1, 3, and 6 mg/kg of body weight. Concentrations were measured by a validated high-performance liquid chromatography method and fitted into a three-compartment open pharmacokinetic model. Across the investigated dosage range, caspofungin displayed dose-independent pharmacokinetics. Following administration over 7 days, the mean peak concentration in plasma (C(max)) +/- standard error of the mean increased from 16.01 +/- 0.61 microg/ml at the 1-mg/kg dose to 105.52 +/- 8.92 microg/ml at the 6-mg/kg dose; the mean area under the curve from 0 h to infinity rose from 13.15 +/- 2.37 to 158.43 +/- 15.58 microg. h/ml, respectively. The mean apparent volume of distribution at steady state (Vd(ss)) was 0.299 +/- 0.011 liter/kg at the 1-mg/kg dose and 0.351 +/- 0.016 liter/kg at the 6-mg/kg dose (not significant [NS]). Clearance (CL) ranged from 0.086 +/- 0.017 liter/kg/h at the 1-mg/kg dose to 0.043 +/- 0.004 liter/kg/h at the 6-mg/kg dose (NS), and the mean terminal half-life was between 30 and 34 h (NS). Except for a trend towards an increased Vd(ss), there were no significant differences in pharmacokinetic parameters in comparison to those after single-dose administration. Caspofungin was well tolerated, displayed linear pharmacokinetics that fit into a three-compartment pharmacokinetic model, and achieved sustained concentrations in plasma that were multiple times in excess of reported MICs for susceptible opportunistic fungi.     

Comparing pharmacokinetics of amoxicillin given twice or three times per day to children older than 3 months with pneumonia

For children with ambulatory pneumonia, the World Health Organization (WHO) recommends oral amoxicillin (15 mg/kg of body weight/dose) thrice daily (t.i.d.) or oral cotrimoxazole (4 mg of trimethoprim/kg/dose) twice daily (b.i.d.). The more frequent amoxicillin dosing may lead to compliance problems. To compare the pharmacokinetics and levels of amoxicillin in plasma in the current WHO acute respiratory infection recommendations with the 25-mg/kg/dose b.i.d. regimen, we performed a two-group parallel study of 66 children ages 3 to 59 months with pneumonia. Amoxicillin was given orally at 25 mg/kg/dose b.i.d. or 15 mg/kg/dose t.i.d. Amoxicillin concentrations were determined by high-performance liquid chromatography after the first dose on days 1 and 3. After the first dose on day 1, the mean area under the concentration-time curve (AUC) for amoxicillin after the 25-mg/kg dose was 54.7 versus 24.9 micro g. h/ml after the 15-mg/kg dose. After the first dose on day 3, the mean AUC was 44.1 versus 28.5 micro g. h/ml. All but two children had plasma amoxicillin concentrations above 0.5 micro g/ml for >50% of the dose interval on both days. Six children on day 1 and five children on day 3 had concentrations above 1.0 micro g/ml for <50% of the dose interval. On day 1, 16 of 27 children in the b.i.d. group and 11 of 26 children in the t.i.d. group had concentrations that were above 2.0 micro g/ml for <50% of the dose interval, and on day 3, 18 of 31 children in the b.i.d. group and 8 of 31 children in the t.i.d. group had concentrations that were above 2.0 micro g/ml for <50% of the dose interval. Amoxicillin b.i.d. is a feasible alternative for t.i.d. dosing. To lengthen the time above the MIC at higher concentration levels, a 30- to 40-mg/kg/dose b.i.d. should be considered instead of the 25 mg/kg/dose used in this study.     

Compartmental pharmacokinetics and tissue distribution of the antifungal triazole ravuconazole following intravenous administration of its di-lysine phosphoester prodrug (BMS-379224) in rabbits

OBJECTIVES: Ravuconazole is a broad-spectrum antifungal triazole in clinical development. We investigated the compartmental plasma pharmacokinetics and tissue distribution of ravuconazole following administration of its novel intravenous (i.v.) di-lysine phosphoester prodrug, BMS-379224. METHODS: Normal catheterized rabbits received the prodrug at 1.25, 2.5, 5, 10, 20 and 40 mg/kg once daily as 5 min i.v. bolus for 8 days. Serial plasma levels were collected at days 1 and 7, and tissues were obtained 30 min after the eighth dose. Concentrations of ravuconazole were determined by a validated HPLC method. Plasma concentration data were fitted to a three-compartment pharmacokinetic model. Pharmacokinetic parameters were estimated by weighted non-linear least squares regression analysis using the WinNonlin computer program. RESULTS: Following single dosing, ravuconazole demonstrated linear plasma pharmacokinetics across the investigated dosage range. Cmax, AUC(0-infinity), V(ss), CL and terminal half-life (means +/- SEM) ranged from 2.03 to 58.82 mg/L, 5.80 to 234.21 mg x h/L, 5.16 to 6.43 L/kg, 0.25 to 0.18 L/h/kg and 20.55 to 26.34 h, respectively. Plasma data after multiple dosing revealed non-linear disposition at the 20 and 40 mg/kg dosage levels as evidenced by a dose-dependent decrease in CL (from 0.104-0.147 to 0.030 and 0.022 L/h/kg; P = 0.1053) and an increase in the dose-normalized AUC(0-infinity) (from 2.40-3.01 up to 11.90 and 14.56 mg x h/L; P = 0.0382). Tissue concentrations 30 min after the last dose were highest in the liver (12.91-562.68 microg/g), adipose tissue (10.57-938.55 microg/g), lung (5.46-219.12 microg/g), kidney (3.95-252.44 microg/g) and brain tissue (2.37-144.85 microg/g). CONCLUSIONS: The pharmacokinetics of ravuconazole fitted best to a three-compartment pharmacokinetic model. The compound revealed non-linear pharmacokinetics at higher dosages, indicating saturable clearance and/or protein binding. Ravuconazole displayed a long elimination half-life and achieved substantial plasma and tissue concentrations including in the brain.     

Pharmacokinetics of Ertapenem in Critically Ill Patients Receiving Continuous Venovenous Hemodialysis or Hemodiafiltration

This study characterizes the pharmacokinetics of ertapenem, a carbapenem antibiotic, in critically ill adult subjects receiving continuous renal replacement therapy (CRRT). Eight critically ill patients with suspected/known Gram-negative infections receiving continuous venovenous hemodialysis (CVVHD) or continuous venovenous hemodiafiltration (CVVHDF) and ertapenem were enrolled. One gram of ertapenem was infused over 30 min. Predialyzer blood samples were drawn with the first dose of ertapenem from the hemodialysis tubing at time zero, 30 min, and 1, 2, 4, 8, 12, 18, and 24 h after the start of the ertapenem infusion. Effluent was collected at the same time points. Ertapenem total serum, unbound serum, and effluent concentrations from all eight subjects were used simultaneously to perform a population compartmental pharmacokinetic modeling procedure using NONMEM. Monte Carlo simulations were performed to evaluate the ability of several ertapenem dosing regimens (500 mg once daily, 750 mg once daily, 500 mg twice daily, and 1,000 mg once daily) to obtain effective unbound serum concentrations above 0.5, 1, and 2 μg/ml. For our simulated patients, all regimens produced unbound ertapenem concentrations above 2 μg/ml for 40% of the dosing interval for at least 96% of simulated patients. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT00877370","term_id":"NCT00877370"}}NCT00877370.)     

Multiple-dose pharmacokinetics of intravenously administered cefoperazone and sulbactam when given in combination to infected, seriously ill, elderly patients.

The pharmacokinetics of cefoperazone and sulbactam in combination were evaluated in six, elderly, seriously ill patients treated with the drug combination for intra-abdominal infections. After giving informed consent, three males and three females aged 63.5 to 77.5 (mean 67.9) years and weighing 54.5 to 86.8 (mean, 67.6) kg were treated with cefoperazone (2.0 g) and sulbactam (1.0 g) infused intravenously every 12 h for at least 5 days. Cefoperazone and sulbactam pharmacokinetics were characterized on both days 1 and 5 of treatment. Eleven serial blood samples were obtained just prior to and following dose 1 on days 1 and 5 of treatment. Mean estimates of cefoperazone maximal concentration in plasma (Cmax), area under the curve of drug concentration in plasma versus time (AUC), half-life (t 1/2), apparent volume of distribution by the area method (Varea), apparent volume of distribution at steady state (Vss), and total body clearance (CL) for day 1 (day 5) were 297.5 237.5) micrograms/ml, 1,247 (1,063) micrograms.h/ml, 7.0 (4.9) h, 16.1 (13.4) liter, 13.1 (14.4) liter, and 28.9 (34.2) ml/min, respectively. Day 1 (day 5) mean values for sulbactam Cmax, AUC, t 1/2, Varea, Vss, and CL were 110.3 (78.0) micrograms/ml, 228 (217) micrograms.h/ml, 3.4 (2.5) h, 26.1 (18.5) liter, 18.9 (15.4) liter, and 97 (94) ml/min, respectively. Both drugs evidenced slower elimination and greater pharmacokinetic variability in these patients compared with values previously reported for normal volunteers. As patients improved during the course of therapy, the only pharmacokinetic parameter significantly changed between days 1 and 5 was a shortened sulbactam t 1/2. Our inability to find substantial evidence of pharmacokinetic normalization may have been related to sample size and study duration. Both drugs were present in potentially therapeutic concentrations for the entire 12-h dosing interval, but without undue accumulation from days 1 to 5.     

Ertapenem pharmacokinetics and impact on intestinal microflora, in comparison to those of ceftriaxone, after multiple dosing in male and female volunteers

The pharmacokinetics of ertapenem and ceftriaxone were investigated in an open, randomized, two-period crossover study after single- and multiple-dose administration in 10 healthy volunteers (five women and five men). Both antibiotics were administered intravenously once daily for 7 days at dosages of 1 g (ertapenem) and 2 g (ceftriaxone). The concentrations of the antibiotics in serum and urine were quantified by the agar well diffusion method bioassay and, in addition, for ertapenem only, by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). For ertapenem the maximum concentration of the drug in plasma (C(max)) was 256 mg/liter, the half-life was 20.7 h, and the area under the plasma concentration-time curve (AUC) was 830 mg. h/liter. The concentrations in fecal samples were (mean value) 37.2 and 32.7 mg/kg on day 4 and day 8, respectively. Ceftriaxone exhibited a mean C(max) of 315 mg/liter, a half-life of 7.6 h, and an AUC of 1,556 mg. h/liter. The mean concentrations in fecal samples were 153 and 258 mg/kg on day 4 and day 8, respectively. No accumulation of ertapenem or ceftriaxone was detected at steady state. A slightly but significantly decreased AUC for ertapenem was detected for the female volunteers. No serious adverse event was observed. Both antibiotics induced a marked decrease in the anaerobic microflora (4-log-unit decreases in lactobacilli, bifidobacteria, clostridia, and bacteroides) and Escherichia coli, whereas the number of enterococci increased (4 log units). A slight overgrowth of yeasts was observed with both regimens. In all cases the microflora returned to normal levels on days 21 to 35.     

Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers.

The influence of food on itraconazole pharmacokinetics was evaluated for 27 healthy male volunteers in a single-dose (200 mg) crossover study with capsules containing itraconazole-coated sugar spheres. This study was followed by a study of the steady-state pharmacokinetics for the same subjects with 15 days of administration of itraconazole at 200 mg every 12 h. Concentrations of itraconazole and hydroxyitraconazole, the active main metabolite, were measured in plasma by high-performance liquid chromatography. The results of the food interaction segment showed that a meal significantly enhances the amount of itraconazole absorbed. The mean maximum concentration in plasma of unmetabolized itraconazole after fasting (140 ng/ml) was about 59% that after the standard meal (239 ng/ml). The rate of elimination was not affected (terminal half-life, approximately 21 h). The mean maximum concentration in plasma of hydroxyitraconazole after fasting was about 72% the postmeal concentration (287 and 397 ng/ml, respectively). The terminal half-life of hydroxyitraconazole was approximately 12 h. Steady-state concentrations of itraconazole and hydroxyitraconazole were reached after 14 or 15 days of daily dosing. The average steady-state concentrations were approximately 1,900 ng/ml for itraconazole and 3,200 ng/ml for hydroxyitraconazole. The shape of the elimination curve for itraconazole after the last dose was indicative of saturable elimination. This conclusion was confirmed by the sevenfold increase in the area under the curve from 0 to 12 h at steady state compared with the area under the curve from 0 h to infinity after a single dose. It was furthermore confirmed by the larger-than-expected number of half-lives required to achieve steady-state plasma drug levels.     

Single-dose pharmacokinetics of Ro 17-2301 (AMA-1080), a monocyclic beta-lactam, in humans.

Ro 17-2301 (AMA-1080) is a new N-sulfonated monocyclic beta-lactam that is highly active against gram-negative bacteria, especially against Enterobacteriaceae and Haemophilus, Neisseria, and Pseudomonas spp. (Kondo et al., Proc. Int. Congr. Chemother. 13th, Vienna, Austria, p. 56/1-56/5, 1983). The single-dose pharmacokinetics of this compound were studied in six healthy male volunteers who received intravenous infusions of 500, 1,000, and 2,000 mg. A good linear correlation (r2 = 0.99) was found between the dose infused and the resulting area under the plasma concentration-time curve. Maximal plasma concentrations of 36, 78, and 150 micrograms/ml appeared after doses of 500, 1,000, and 2,000 mg, respectively. The mean terminal elimination half-life was 1.8 h (range, 1.4 to 2.3 h), the apparent volume of distribution at steady state was 17 liters, and the total systemic clearance was 150 ml/min. Within 72 h 78 to 89% of the dose was recovered intact from urine. After administration of 14C-labeled Ro 17-2301, 96% of the radioactivity was found in the urine and 3% was found in the feces. The concomitant administration of probenecid did not affect the renal clearance or urinary excretion of this beta-lactam, an indication that the renal elimination of this substance is only by glomerular filtration. Ro 17-2301 was 18% bound to human plasma protein, and this binding was independent of concentration between 25 and 400 micrograms/ml. Based on these data, the pharmacokinetics of this monocyclic beta-lactam should be predictable in the foreseen dose ranges.     

Quantification of the carbapenem antibiotic ertapenem in human plasma by a validated liquid chromatography-mass spectrometry method

BACKGROUND: Ertapenem (Invanz) is a newly developed carbapenem beta-lactam antibiotic. LC-MS is the method of choice for therapeutic drug monitoring (TDM) of a variety of drugs including antibiotics. No validated LC-MS method for ertapenem quantification is described in the literature so far. METHODS: A rapid and robust LC-MS quantification method for ertapenem was developed and validated for clinical routine application in plasma samples. After immediate stabilisation with MES buffer (pH 6.5), samples were prepared for LC-MS analysis using simple protein precipitation. LC-MS coupling was realised by the use of a Phenomenex Synergi 4micro Polar-RP A80 Mercury LC column (10 x 2.0 mm) in combination with a Single-MS (Agilent 1100 LC-MSD SL) operating in negative selected ion monitoring (SIM) detection mode with ceftazidime as internal standard for adequate selective and sensitive analysis. RESULTS: LC-MS method validation by means of determination of limit of detection (LOD 0.1 microg mL-1), lower limit of quantification (LLOQ 1 microg mL-1), linearity (0.1-50 microg mL-1), recovery (> 90%), intra- and inter-day precision (RSD < 10%), accuracy (> 90%), inter-subject variability (< 10% at LLOQ), drug stability in plasma (> 3 months) and in post-extracted samples (> 99% for 24 h), and matrix effects (process efficiency > 90%) showed excellent performance parameters considering Guidance for Industry - Bioanalytical Method Validation. CONCLUSION: This method is perfectly appropriate for routine quantification of ertapenem and possibly other polar carbapenem beta-lactam antibiotics.