Safety, Tolerance and Pharmacokinetics of 2.0 g Cefpirome (HR 810) after Single and Multiple Dosing

Badian, M; Malerczyk, V.; Collins, Janice; Dixon, Graham; Verho, M; Eckert, Hans-Georg

doi:10.1159/000238594

Cited by 16 publications

(9 citation statements)

References 3 publications

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“…The estimates from our NONMEM and S-ADAPT population PK analyses agreed excellently (Table 3) and were consistent with PK data on cefpirome in the treatment of healthy volunteers in other studies (3,25,41,46,48,54,59). Our population PK model exhibited a highly sufficient predictive performance for cefpirome in plasma and urine (Fig.…”

Section: Vol 55 2011 Population Pk Of Cefpirome In Cystic Fibrosis supporting

confidence: 87%

“…All blood samples were drawn from a forearm vein via an intravenous catheter contralateral to the one used for dosing. For all subjects, blood samples were drawn immediately before start of the infusion (0 min), at 5 and 10 min after the start of infusion, and at 5, 10, 15, 20, and 30 min and 0.75, 1, 1.25, 1.5, 2, 2.5, 3,4,5,6,7,8,10,12,16, and 24 h after the end of infusion. Samples were cooled in ice water for approximately 10 to 15 min before centrifugation.…”

Section: Subjectsmentioning

confidence: 99%

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Comparable Population Pharmacokinetics and Pharmacodynamic Breakpoints of Cefpirome in Cystic Fibrosis Patients and Healthy Volunteers

Bulitta¹,

Kinzig²,

Landersdorfer³

et al. 2011

Antimicrob Agents Chemother

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Cystic fibrosis (CF) patients are often reported to have higher clearances and larger volumes of distribution per kilogram of total body weight (WT) for beta-lactams than healthy volunteers. As pharmacokinetic (PK) data on cefpirome from studies of CF patients are lacking, we systematically compared its population PK and pharmacodynamic breakpoints for CF patients and healthy volunteers of similar body size. Twelve adult CF patients (median lean body mass [LBM] ‫؍‬ 45.7 kg) and 12 healthy volunteers (LBM ‫؍‬ 50.0 kg) received a single 10-min intravenous infusion of 2 g cefpirome. Plasma and urine concentrations were determined by high-performance liquid chromatography (HPLC). Population PK and Monte Carlo simulations were performed using NONMEM and S-ADAPT and a duration of an unbound plasma concentration above the MIC > 65% of the dosing interval as a pharmacodynamic target. Unscaled clearances for CF patients were similar to those seen with healthy volunteers, and the volume of distribution was 6% lower for CF patients. Linear scaling of total clearance by WT resulted in clearance that was 20% higher (P < 0.001 [nonparametric bootstrap]) in CF patients. Allometric scaling by LBM explained the differences between the two subject groups with respect to average clearance and volume of distribution and reduced the unexplained between-subject variability of renal and nonrenal clearance by 10 to 14%. For the CF patients, robust (>90%) probabilities of target attainment (PTA) were achieved by the administration of a standard dose of 2 g/70 kg WT every 12 h (Q12h) given as 30-min infusions for MICs < 1.5 mg/liter. As alternative dosage regimens, a 5-h infusion of 1.33 g/70 kg WT Q8h achieved robust PTAs for MICs < 8 to 12 mg/liter and a continuous infusion of 4 g/day for MICs < 12 mg/liter. Prolonged infusion of cefpirome is expected to be superior to short-term infusions for MICs between 2 and 12 mg/liter.

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Section: Vol 55 2011 Population Pk Of Cefpirome In Cystic Fibrosis supporting

confidence: 87%

Section: Subjectsmentioning

confidence: 99%

Comparable Population Pharmacokinetics and Pharmacodynamic Breakpoints of Cefpirome in Cystic Fibrosis Patients and Healthy Volunteers

Bulitta¹,

Kinzig²,

Landersdorfer³

et al. 2011

Antimicrob Agents Chemother

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“…This is in marked contrast to cefoperazone (5), cefotaxime (5), ceftriaxone (13), and ceftizoxime (11), of which only 25, 55, 60, and 70% of the administered dose is recovered intact in the urine, respectively. The %oXu for cefepime is very similar to those reported for ceftazidime (3,8,15) and cefpirome (1,10). Mean CLR estimates for cefepime are about 105 ml/min, a value very similar to that of creatinine clearance in young healthy humans.…”

Section: Discussionsupporting

confidence: 78%

“…The t1/2 of cefepime was approximately 2 h and did not appear to vary over the 250-to 2,000-mg-dose range. The t1/2 value of cefepime is very similar to those for ceftazidime (3,8,15) and cefpirome (1,10).…”

Section: Discussionsupporting

confidence: 61%

Safety, tolerance, and pharmacokinetic evaluation of cefepime after administration of single intravenous doses

Barbhaiya

Forgue

Gleason

et al. 1990

Antimicrob Agents Chemother

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In this double-blind, single-dose phase I study, the safety and tolerance of cefepime were assessed in 24 healthy male subjects, with ceftazidime as the control drug. Four subjects in each of the six dose groups (62.5, 125, 250, 500, 1,000, or 2,000 mg as a 30-min itravenous infusion) received each antibiotic, according to*a crossover design, with a 2-day washout period between treatments. Blood and urine samples were obtained to characterize the pharmacokinetics of cefepime. Plasma and urine samples were assayed for intact cefepime. Samples containing ceftazidime were discarded. The adverse effects observed in the study were mild and infrequent, with prompt recovery from adverse experiences and abnormal laboratory values. The cefepime pharmacokinetic parameters for the therapeutically significant doses of 250 to 2,000 mg appeared to be proportional to dose and similar to literature values for ceftazidime. The elimination half-life of about 2 h was independent of the dose. Urinary recovery of intact cefepime was invariant with respect to dose; an overall mean value of 82% of dose was obtained for the four highest levels. Mean renal clearance was 105 mI/min and suggestive of glomerular filtration as the primary excretion mechanism. In normal humans, the safety and pharmacokinetic profiles of cefepime are very similar to those of ceftazidime.Cefepime (BMY-28142; Bristol-Myers Squibb Co.) is a "fourth-generation" cephalosporin antibiotic with significant potential advantages over other broad-spectrum cephalosporins and some nontraditional beta-lactam antibiotics (4, 9, 18). It differs from other aminothiazolyl methoxyimino cephalosporins by having a quaternized N-methyl pyrrolidine moiety attached to the methylene group at C-3 (Fig. 1). In addition to a very broad antimicrobial spectrum, cefepime appears to have low affinity for major chromosomally mediated ,3-lactamases and thus is less affected by the nonhydrolytic barrier mechanism of resistance in these bacteria (14). These in vitro advantages have been borne out in a number of in vivo infection models (9,17).Preclinical safety evaluation and pharmacokinetic studies of cefepime were done primarily with rats and monkeys. The findings of these studies suggest that when administered by intravenous infusion, cefepime is as safe as other commercially available cephalosporins. The pharmacokinetics in rats and monkeys have been extensively characterized (2, 7). The present phase I study was designed to evaluate the safety, tolerance, and pharmacokinetics of cefepime in healthy male volunteers. MATERIALS AND METHODSStudy design. The purposes of this study were to evaluate the safety and tolerance of cefepime after single intravenous doses of 62.5, 125, 250, 500, 1,000, and 2,000 mg to normal human volunteers. The pharmacokinetics of cefepime were also assessed at each dose level. The study was

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“…At therapeutic levels [1], the new drug shows greater inhibition activity in particular against oxacillin-resistant S. aureus, Enterococci, and P. aeruginosa.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory and Bactericidal Activity of Cefpirome and Cefotaxime against Blood Culture Isolates

Ansorg¹,

Primavesi²,

Recklinghausen³

1990

Chemotherapy

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Using a broth microtiter dilution method, minimum inhibitory (MIC) and minimum bactericidal concentrations (MBC) were determined for the aminothiazolyl cephalosporins cefpirome and cefotaxime against 436 blood culture isolates. At concentrations of ≤16 mg/l, cefpirome inhibited 82.3% of the isolates and cefotaxime 66.5%. At the same concentrations, cefpirome killed 60.0% of the isolates and cefotaxime 46.7%. Whereas the MIC values indicated a far better activity of cefpirome than cefotaxime against oxacillin-resistant Staphylococcus aureus, Enterococci and Pseudomonas aeruginosa, the MBC values showed a poor activity of both drugs against these strains. By comparison, cefpirome was the more active agent, covering a similar spectrum to that of cefotaxime with a slight additional activity against oxacillin-susceptible 5. aureus and Staphylococcus epidermidis.

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Safety, Tolerance and Pharmacokinetics of 2.0 g Cefpirome (HR 810) after Single and Multiple Dosing

Cited by 16 publications

References 3 publications

Comparable Population Pharmacokinetics and Pharmacodynamic Breakpoints of Cefpirome in Cystic Fibrosis Patients and Healthy Volunteers

Comparable Population Pharmacokinetics and Pharmacodynamic Breakpoints of Cefpirome in Cystic Fibrosis Patients and Healthy Volunteers

Safety, tolerance, and pharmacokinetic evaluation of cefepime after administration of single intravenous doses

Inhibitory and Bactericidal Activity of Cefpirome and Cefotaxime against Blood Culture Isolates

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