Individualized Cefepime Dosing Study

NCT ID: NCT02680600

Last Updated: 2016-02-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-03-31
• Study Completion Date: 2016-01-31

Brief Summary

Several population pharmacokinetic (PK) models for cefepime in critically ill patients have been described, all indicating that variability in renal clearance is the main determinant of observed variability in exposure. The main objective of this study was hence to determine which renal marker best predicts cefepime clearance.

Detailed Description

Timely and appropriate antibiotic therapy, sufficient to guarantee adequate antibiotic concentrations in blood and tissues, is one of the most important interventions in critically ill patients with infections.1,2 Cefepime is a fourth generation cephalosporin with broad spectrum activity against Gram-negative bacteria that is used as empirical and directed therapy for severe infections like sepsis and pneumonia. Nevertheless, administration of adequate antibiotic doses is a real challenge in critically ill patients because the pharmacokinetics (PK) of these drugs may be influenced by the complex pathophysiological changes that occur during sepsis.2 Recent reviews described the enormous pharmacokinetic variability of beta-lactam antibiotics in critically ill patients.3,4 Therefore, strategies for dose individualization are explored in an attempt to better control a patient's exposure to the antibiotic, thereby potentially improving the prognosis of critically ill patients with infection. On the one hand, several smaller studies have already shown that better outcomes for critically ill patients can be expected with higher drug exposures, at least for less severely ill patients.5,6 This conclusion was supported by the DALI study, a large multi-center prospective study.7 On the other hand, it was shown that insufficient antibiotic exposure may lead to the development of antibiotic resistance.8 This link was initially shown with inappropriately low quinolone exposures, but more recently with other classes of antibiotics including beta-lactams.9,10 In addition to ensuring that plasma levels are high enough for optimal antimicrobial activity and suppressing emergence of resistance, individualized dosing might offer a perspective to prevent potential side-effects originating from toxic plasma levels. This seems particularly relevant for cefepime, a beta-lactam antibiotic, as it was shown that cefepime is an underappreciated cause of neurotoxicity, especially in intensive care unit (ICU) patients,11,12 patients with impaired renal function,13-16 and patients with brain disorders.17 Population pharmacokinetic models provide a quantitative view of the effect of particular individual factors on the plasma concentration time profile of a drug. Population PK models thereby help to establish individual treatment regimen in patients, depending on the specific patient covariates that were included in the model. As cefepime is a hydrophilic compound, drug elimination is mainly determined by renal clearance and to a lesser extent by non-renal clearance. Therefore, renal markers have been explored as the main determinant to predict cefepime variability in population PK models.18-24 However, none of the published PK models was developed using both plasma and urinary data, though having access to both matrices may be an advantage to identify clinically relevant covariates. Moreover, only creatinine-based markers were used as covariates and, up to now, it was unclear whether the newer markers to assess renal function (e.g. cystatine C, uromodulin and Kidney Injury Moleclure-1 (KIM-1)) are more accurate to predict cefepime clearance.

In this study, a clinical trial was conducted to develop a population PK model for cefepime in critically ill patients assessing renal and non-renal clearance separately, based on both plasma and urinary cefepime concentrations. This model then served as a tool to compare the adequacy of six different renal markers as predictors for renal cefepime clearance. After integrating the most adequate predictor into the PK model, the final model was used to evaluate current dose recommendations for cefepime.

Conditions

Antimicrobial Treatment

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Study arm

• Cefepime dosing
• Blood sampling
• Urine sampling
• Determination of renal markers
• Population pharmacokinetic modeling
• Covariate screening
• Monte Carlo simulations

Group Type: EXPERIMENTAL

Cefepime dosing

Intervention Type: DRUG

Patients will received cefepime administered per standard-of-care as a 30 min intravenous infusion. Dosing will be based on local guidelines (the Sanford guide to antimicrobial therapy 2012-2013) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine formula to estimate glomerular filtration rate (GFR).

Blood sampling

Intervention Type: OTHER

Blood will be sampled immediately prior to dose administration (time = 0 at the start of the 30 min infusion), at 0.5, 1, 3, 5 hours post-start of infusion and just before the subsequent dose. From day two onwards, samples will be taken at the end of the infusion and just before the next dose. For the quantification of cefepime, a validated solid phase extraction-liquid chromatography electrospray-tandem mass spectrometry method will be used.

Urine sampling

Intervention Type: OTHER

Timed urine collections were taken during one dosing interval (8 hours in a three times daily regimen) every day.

Determination of renal markers

Intervention Type: OTHER

Creatinine (modified Jaffe method) and urea in serum will be determined using an Architect c16000 analyzer (Abbott, Chicago, IL, USA). Cystatin C will be determined using a particle-enhanced immunonephelometric assay (N Latex Cystatin C, Siemens Healthcare Diagnostics, Marburg, Germany) by use of a BN II nephelometer (Siemens Healthcare Diagnostics). This assay has a calibration traceable to the first certified reference material for cystatin C in human serum (ERM-DA471/IFCC). Kidney injury molecule-1 (KIM-1) in urine and uromodulin in serum will be determined using commercially available ELISA assays: Quantikine ELISA Human TIM-1/KIM-1/HAVCR (R\&D Systems, Minneapolis, MN, USA) and Uromodulin ELISA (Euroimmun, Luebeck, Germany), respectively.

Population pharmacokinetic modeling

Intervention Type: OTHER

The cefepime concentration versus time data will be fitted using the FOCE-I estimation algorithm in NONMEM® (Version 7.3; GloboMax LLC, Hanover, MD, USA). R® (R foundation for statistical computing, Vienna, Austria) will be used to graphically assess the model's goodness-of-fit and to evaluate the model's predictive capabilities. As a measure of prediction error, the absolute prediction error (APE) will be used. In short, the measured cefepime concentrations for each individual i at time point j were compared against the population predicted cefepime concentrations, i.e. the predictions for each individual without taking into account the between-subject variability (PRED in NONMEM). The distribution of APEs will be summarized by the median and 90% percentile.

Covariate screening

Intervention Type: OTHER

Renal function will be assessed by four serum based kidney markers (serum creatinine, cystatin C, urea and uromodulin) and two urinary markers (measured creatinine clearance (CrCl) and KIM-1, both on timed urine collections). Serum creatinine and cystatin C will also be used to calculate the eGFR based on CKD-EPI formulas.

Monte Carlo simulations

Intervention Type: OTHER

Based on the final covariate model, a Monte Carlo-based simulation study will be performed to evaluate the Sanford dose recommendations for ICU patients.

Interventions

Cefepime dosing

Patients will received cefepime administered per standard-of-care as a 30 min intravenous infusion. Dosing will be based on local guidelines (the Sanford guide to antimicrobial therapy 2012-2013) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine formula to estimate glomerular filtration rate (GFR).

Intervention Type: DRUG

Blood sampling

Blood will be sampled immediately prior to dose administration (time = 0 at the start of the 30 min infusion), at 0.5, 1, 3, 5 hours post-start of infusion and just before the subsequent dose. From day two onwards, samples will be taken at the end of the infusion and just before the next dose. For the quantification of cefepime, a validated solid phase extraction-liquid chromatography electrospray-tandem mass spectrometry method will be used.

Intervention Type: OTHER

Urine sampling

Timed urine collections were taken during one dosing interval (8 hours in a three times daily regimen) every day.

Intervention Type: OTHER

Determination of renal markers

Creatinine (modified Jaffe method) and urea in serum will be determined using an Architect c16000 analyzer (Abbott, Chicago, IL, USA). Cystatin C will be determined using a particle-enhanced immunonephelometric assay (N Latex Cystatin C, Siemens Healthcare Diagnostics, Marburg, Germany) by use of a BN II nephelometer (Siemens Healthcare Diagnostics). This assay has a calibration traceable to the first certified reference material for cystatin C in human serum (ERM-DA471/IFCC). Kidney injury molecule-1 (KIM-1) in urine and uromodulin in serum will be determined using commercially available ELISA assays: Quantikine ELISA Human TIM-1/KIM-1/HAVCR (R\&D Systems, Minneapolis, MN, USA) and Uromodulin ELISA (Euroimmun, Luebeck, Germany), respectively.

Intervention Type: OTHER

Population pharmacokinetic modeling

The cefepime concentration versus time data will be fitted using the FOCE-I estimation algorithm in NONMEM® (Version 7.3; GloboMax LLC, Hanover, MD, USA). R® (R foundation for statistical computing, Vienna, Austria) will be used to graphically assess the model's goodness-of-fit and to evaluate the model's predictive capabilities. As a measure of prediction error, the absolute prediction error (APE) will be used. In short, the measured cefepime concentrations for each individual i at time point j were compared against the population predicted cefepime concentrations, i.e. the predictions for each individual without taking into account the between-subject variability (PRED in NONMEM). The distribution of APEs will be summarized by the median and 90% percentile.

Intervention Type: OTHER

Covariate screening

Renal function will be assessed by four serum based kidney markers (serum creatinine, cystatin C, urea and uromodulin) and two urinary markers (measured creatinine clearance (CrCl) and KIM-1, both on timed urine collections). Serum creatinine and cystatin C will also be used to calculate the eGFR based on CKD-EPI formulas.

Intervention Type: OTHER

Monte Carlo simulations

Based on the final covariate model, a Monte Carlo-based simulation study will be performed to evaluate the Sanford dose recommendations for ICU patients.

Intervention Type: OTHER

Other Intervention Names

Cefepime administration

Eligibility Criteria

Inclusion Criteria

• Patient age 18 years or more
• Hospitalized in the ICU of OLV hospital Aalst
• Elected by the treating physician to receive cefepime,irrespectively of the study
• Presence of arterial or central line for blood sampling

Exclusion Criteria

• Exact time of cefepime administration or blood sampling unknown
• No written informed consent by the patient or his/her (legal) representative

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Ghent

OTHER

Sponsor Role: collaborator

Onze Lieve Vrouw Hospital

OTHER

Sponsor Role: lead

Responsible Party

Stijn Jonckheere

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Stijn Jonckheere

Role: PRINCIPAL_INVESTIGATOR

Onze Lieve Vrouw Hospital

References

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Other Identifiers

B126201419859

Identifier Type: -

Identifier Source: org_study_id