Pharmacokinetics of Ceftaroline in Normal Body Weight and Obese (Classes I, II, and III) Healthy Adult Subjects

Justo, Julie Ann; Mayer, Stockton; Pai, Manjunath P.; Soriano, Melinda M.; Danziger, Larry H.; Novak, Richard M.; Rodvold, Keith A.

doi:10.1128/aac.00498-15

Cited by 29 publications

(34 citation statements)

References 28 publications

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“…As far as plasma is concerned, Table 2 shows that the values of the key PK parameters of CPT after administration q12h (i.e., the currently recommended dosing regimen) were in line with the values from the recent literature (21,22). In comparison, administration of CPT-F q8h produced significantly higher AUC 0 -24 and, more importantly, fT MIC values.…”

Section: Discussionsupporting

confidence: 72%

Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil

Matzneller

Lackner

Lagler

et al. 2016

Antimicrob Agents Chemother

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bCeftaroline fosamil (CPT-F) is currently approved for use for the treatment of complicated skin and soft tissue infections and community-acquired pneumonia at 600 mg twice daily (q12h), but other dosing regimens are under evaluation. To date, very limited data on the soft tissue pharmacokinetics (PK) of the active compound, ceftaroline (CPT), are available. CPT concentrations in the plasma, muscle, and subcutis of 12 male healthy volunteers were measured by microdialysis after single and repeated intravenous administration of 600 mg CPT-F q12h or three times daily (q8h) in two groups of 6 subjects each. Relevant PK and PK/pharmacodynamic (PD) parameters were calculated and compared between groups. In plasma, the area under the concentration-time curve (AUC) from 0 to 24 h for total CPT and the cumulative percentage of the dosing interval during which the free drug concentrations exceeded the MIC (fT MIC ) for unbound CPT for the currently established threshold of 1 mg/liter were significantly higher in the group receiving CPT-F q8h. Exposure to free drug in soft tissues was higher in the group receiving CPT-F q8h, but high interindividual variability in relevant PK parameters was observed. The mean ratios of the AUC from time zero to the end of the dosing interval (AUC 0-) for free CPT in soft tissues and the AUC 0-for the calculated free fraction in plasma at steady state ranged from 0.66 to 0.75. Administration of CPT-F q8h led to higher levels of drug exposure in all investigated compartments. When MIC values above 1 mg/liter were assumed, the calculated fT MIC after dosing q12h was markedly lower than that after dosing q8h. The clinical implications of these differences are discussed in light of recently completed clinical phase III and PK/PD studies. Ceftaroline fosamil (CPT-F; brand names, Zinforo in Europe and Teflaro in the United States) was recently approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of complicated skin and soft tissue infections (cSSTIs) and community-acquired pneumonia (CAP) in adults. Ceftaroline (CPT) is a cephalosporin antibiotic and acts, like all beta-lactam agents, via inhibition of peptidoglycan synthesis. In contrast to other cephalosporins, CPT is active against some resistant microorganisms, such as methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-nonsusceptible Streptococcus pneumoniae (PNSP), and is therefore often referred to as a "fifth generation," or advanced-generation, cephalosporin. CPT-F, a water soluble N-phosphono prodrug, is converted to the active CPT in human plasma, and CPT is further converted into the inactive ring-opened metabolite CPT M-1.Although CPT-F was shown to be effective against both approved indications, CAP and cSSTIs (1-5), precise information regarding the pharmacokinetics (PKs) of CPT in the interstitial space fluid of soft tissues is very limited to date. However, this information is considered to be highly relevant as a key input for PK/pharmacodynamic (PD) cal...

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Section: Discussionsupporting

confidence: 72%

Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil

Matzneller

Lackner

Lagler

et al. 2016

Antimicrob Agents Chemother

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“…A phase I PK study of ceftaroline 600 mg every 12 hours showed that while Vd and Cl were significantly increased in those with a BMI higher than 40 mg/m 2 , Monte Carlo simulations predicted excellent stasis target exposure (30% ƒT ≥ MIC) with MIC of 1 mg/L or lower that would be adequate concerning most clinical isolates of Staphylococcus aureus, Streptococcus pneumoniae, and non-extended-spectrum b-lactamaseproducing Escherichia coli or Klebsiella spp. 37 They concluded that higher doses (e.g., every 8 hours) may be considered if targeting 50% fT ≥ MIC for methicillin-resistant S. aureus (MRSA), but this warrants further studies. These results are in line with clinical success reported from retrospective registry data of ceftaroline 600 mg every 12 hours dosing in diabetic foot infections or skin and skin structure infections that included obese patients.…”

Section: Ceftarolinementioning

confidence: 99%

Comprehensive Guidance for Antibiotic Dosing in Obese Adults

et al. 2017

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Physiologic alterations seen in obesity commonly impact the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics and may result in suboptimal dosing in this expanding but understudied population. Much of the published clinical and PK evidence to date consists of small patient populations and are retrospective with, not infrequently, heterogeneous results that in some cases are contradictory. In the last 10 years, additional antimicrobial PK/PD and clinical data encompassing prolonged infusion strategies and examination of critically ill populations have emerged to inform antimicrobial dosing in obesity. In this narrative review, we critically review literature on dosing, PK, and possible dosing strategies in obese adults. We searched PubMed, Scopus, and the Cochrane Library using Medical Subject Headings including anti-infectives, specific antimicrobial names, obese, pharmacokinetics, and others. We reviewed articles, cross-referenced select cited references, and when applicable, referenced drug databases and package inserts to develop dosing recommendations. We provide an overall critical review of the available data regarding PK and dosing issues including dosing recommendations in both critically ill and noncritically ill patients with significant obesity. We developed dosing recommendations for 34 antimicrobials based on 121 articles of the 2336 identified by the search strategy. Although 11 of these do not appear to require dose adjustment, obesity-specific dosing guidance is provided for the remaining 23 antimicrobials. Additional studies are needed to better understand and resolve discrepant published results regarding the PK of antibiotics to establish optimal dosing strategies in obese adults. Alternative dosing strategies, such as extended infusions, should be considered for time-dependent antibiotics (e.g., β-lactams) in obese patients to achieve PD targets reliably. Therapeutic drug monitoring across the spectrum of antimicrobials is of increasing importance in this and other populations to ensure optimized dosing.

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“…Monte Carlo simulations of q12h administration of ceftaroline fosamil conducted by Justo et al using a population PK model developed with data from normal-weight to obese healthy subjects found that in the case of MRSA, the cumulative fractions of response were Ͼ90% for 30% and 40% fTϾMIC targets, and 87.5% was predicted for 50% fTϾMIC (23). The study concluded that the 600 mg q12h regimen was adequate against most clinical isolates; however, more frequent dosing (i.e., q8h) or the use of combination therapy may be more suitable for serious, deep-seated infections due to MRSA.…”

Section: Discussionmentioning

confidence: 99%

Penetration of Ceftaroline into the Epithelial Lining Fluid of Healthy Adult Subjects

Riccobene¹,

Pushkin²,

Jandourek³

et al. 2016

Antimicrob Agents Chemother

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c Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with bactericidal activity against Grampositive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to (i) evaluate ceftaroline concentrations in human plasma and epithelial lining fluid (ELF) and (ii) develop a population pharmacokinetic (PK) model for plasma and ELF to be used in PK/pharmacodynamic (PD) target attainment simulations. Ceftaroline concentrations in ELF and plasma at steady state (day 4) were measured in healthy adult subjects for two dosages: 600 mg every 12 h (q12h) and 600 mg every 8 h (q8h). Both were well tolerated with no serious adverse events. The penetration of free ceftaroline into ELF, assuming 20% protein binding in plasma and no protein binding in ELF, was Ϸ23%. The population PK model utilized a two-compartment model for both ceftaroline fosamil and ceftaroline. Goodness-of-fit criteria revealed the model was consistent with observed data and no systematic bias remained. At 600 mg q12h and a MIC of 1 mg/liter, 98.1% of simulated patients would be expected to achieve a target free drug concentration above the MIC (fT>MIC) in plasma of 42%, and in ELF 81.7% would be expected to achieve a target fT>MIC of 17%; at 600 mg q8h, 100% were predicted to achieve an fT>MIC in plasma of 42% and 94.7% to achieve an fT>MIC of 17% in ELF. The literature and data suggest the 600 mg q12h dose is adequate for MICs of <1 mg/liter. There is a need for clinical data in patients with MRSA pneumonia and data to correlate PK/PD relationships in ELF with clinical outcomes. C eftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin antibiotic with bactericidal activity against Gram-positive organisms, including penicillin-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA) (1, 2). Ceftaroline is also active in vitro against Gram-negative organisms such as Haemophilus influenzae and Moraxella catarrhalis and non-extended-spectrum ␤-lactamaseproducing Enterobacteriaceae (1, 2). Ceftaroline fosamil is approved in the United States for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP), with approval in Europe for similar indications. At a dosage of 600 mg every 12 h (q12h), ceftaroline fosamil demonstrated noninferiority to ceftriaxone given at 1 g q24h in the treatment of patients with moderate to severe CABP in two phase 3 clinical studies (ClinicalTrials registration no. NCT00621504 and NCT00509106) (3-5). Ceftaroline fosamil (600 mg q12h) has also been demonstrated to be superior to ceftriaxone (2 g q24h) in the treatment of Asian patients with community-acquired pneumonia (ClinicalTrials registration no. NCT01371838) (6), and in a recent meta-analysis ceftaroline fosamil was shown to be superior to ceftriaxone as an empirical treatment for adult patients hospitalized with PORT risk class 3 to 4 community-acquired pneumonia (7). Ceftaro...

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Pharmacokinetics of Ceftaroline in Normal Body Weight and Obese (Classes I, II, and III) Healthy Adult Subjects

Cited by 29 publications

References 28 publications

Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil

Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil

Comprehensive Guidance for Antibiotic Dosing in Obese Adults

Penetration of Ceftaroline into the Epithelial Lining Fluid of Healthy Adult Subjects

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