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Temocillin Pharmacokinetic in Hemodialysis

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02285075
First Posted: November 6, 2014
Last Update Posted: January 5, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Paul Tulkens, Louvain drug research institute, belgium
Francoise Van Bambeke, Louvain drug research institute, belgium
Ana Miranda Bastos, Louvain drug research institute, belgium
Information provided by (Responsible Party):
Vandecasteele Stefaan Johan, AZ Sint-Jan AV
  Purpose
The current study aimed to explore the pharmacokinetics of temocillin in patients treated with haemodialysis and to demonstrated whether or not the pharmacodynamics target of a time above a MIC of 16 mg/L of more than 40 and 60 % of the dosing interval could be obtained with a dosing schedule of 1 gram/24 hours, 2 gram/48 hours and 3 gram/72 hours, all of these doses given after haemodialysis sessions only.

Condition Intervention Phase
Gram-Negative Bacterial Infections Renal Failure Chronic Requiring Hemodialysis Drug: temocillin PK/PD in haemodialysis Phase 4

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Clinical Pharmacokinetic Study: Is Three Times Weekly Temocillin Appropriate for the Treatment of Severe Gram-negative Infections in Patients With ESRD Treated With Intermittent Hemodialysis?

Resource links provided by NLM:


Further study details as provided by Vandecasteele Stefaan Johan, AZ Sint-Jan AV:

Primary Outcome Measures:
  • % of the dosing interval time above an MIC of 8 and 16 mg/L (% T>MIC 8 or 16 mg/L) [ Time Frame: two to ten days ]
    Is T > MIC 8 and 16 mg/ML > 40 or 60 %


Secondary Outcome Measures:
  • Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis [ Time Frame: two to ten days ]
    Vd (volume of distribution)

  • Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis [ Time Frame: two to ten days ]
    T1/2 (serum half life, on and of dialysis)

  • Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis [ Time Frame: two to ten days ]
    Temocillin clearance (renal and non-renal)

  • Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis [ Time Frame: two to ten days ]
    Temocillin reduction rate

  • Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis [ Time Frame: two to ten days ]
    temocillin removal rate

  • Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis [ Time Frame: two to ten days ]
    temocillin protein binding


Enrollment: 16
Study Start Date: June 2011
Study Completion Date: December 2014
Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
temocillin PK/PD in haemodialysis
Pharmacokinetic study measuring total and free temocillin concentrations in patients treated with haemodialysis receiving 1 gram temocillin for a 1 day interval, 2 gram temocillin for a two day interval and 3 gram temocillin for a 3 day interval to the next dialysis session
Drug: temocillin PK/PD in haemodialysis
Pharmacokinetic study measuring total and free temocillin concentrations just before, and at 0.5, 3, 6, 12, 20 (before dialysis) and 24 (at the end of dialysis) hours after start of the infusion when patients were dialysed with a 1-day interval; just before and at 0.5, 3, 6, 12, 24, 36, 44 (before dialysis) and 48 (at the end of dialysis) hours after start of the infusion when patients were dialysed with a 2-day interval, and just before and at 0.5, 3, 6, 12, 24, 36, 48, 68 (before dialysis) and 72 (at the end of dialysis) hours after start of the infusion if patients were dialysed with a 3-day interval in order to determine basic PK and PD parameters in patients treated with intermittent haemodialysis and temocillin (Vd, T1/2, protein binding, clearance, reduction rate and T > MIC of 8 and 16 mg/L).

Detailed Description:

Background: Temocillin is a renally cleared penicillin with long serum half-live and potent activity against most gram-negative bacteria, making it an ideal candidate for treatment given on dialysis days only of severe gram-negative infections in patients with ESRD treated with haemodialysis.

Endpoints:

Primary: The current study aimed to demonstrated by measurement of AUC whether or not the pharmacodynamics target of a time above a MIC of 8 and 16 mg/L of more than 40 and 60 % of the dosing interval could be obtained with a dosing schedule of 1 gram/24 hours, 2 gram/48 hours and 3 gram/72 hours, all of these doses given after haemodialysis sessions only.

Secondary: Key pharmacokinetic and dialytic parameters were determined as previously described16. The following parameters were recorded: the volume of distribution Vd (determined as Vd = dose / (Tempeak - Temtrough) in liter); the Vd/Wt (in liter/kg body weight); the non-dialysis clearance of temocillin (Ke(non-dialysis) = [ln(Tempeak) - ln(Tempre)] / time between peak level and start of next dialysis); the non-dialysis half-life (T1/2(non-dialysis) = 0.693 / Ke(non-dialysis) in hours); the dialysis clearance of temocillin (Ke(dialysis) = [ln(Tempre) - ln(Tempost)] / dialysis duration); the dialysis half-life (T1/2(dialysis) = 0.693 / Ke(dialysis) in hours); the Urea Reduction Ratio (URR = (BUNpre - BUNpost) / BUNpre); the Temocillin Reduction Ratio TRR = (Tempre - Tempost) / Tempre); the Temocillin Removal Ratio (the total amount of temocillin recovered in the dialysate, based on the area under the curve of the temocillin removal rate and the treatment time); and the AUC of temocillin. For all PK/PD analysis, the non-compartmental method using RStudio 0.98.501 with R 3.0.2 software was used.

Methods: Pharmacokinetic study measuring total and free temocillin concentrations in patients treated with intermittent haemodialysis and temocillin. Blood samples were drawn just before, and at 0.5, 3, 6, 12, 20 (before dialysis) and 24 (at the end of dialysis) hours after start of the infusion when patients were dialysed with a 1-day interval; just before and at 0.5, 3, 6, 12, 24, 36, 44 (before dialysis) and 48 (at the end of dialysis) hours after start of the infusion when patients were dialysed with a 2-day interval, and just before and at 0.5, 3, 6, 12, 24, 36, 48, 68 (before dialysis) and 72 (at the end of dialysis) hours after start of the infusion if patients were dialysed with a 3-day interval. Patients were followed for 1 to 6 subsequent AUC. Dialysate samples were taken 1, 2, 3 and 4 h after the start of dialysis. All samples were taken from an arterial or venous catheter, after thorough rinsing. Serum (obtained by centrifugation after blood clotting) and dialysate was frozen (-80 C) immediately after sampling until analysis.

Temocillin total and free concentrations were determined with high performance liquid chromotography(HPLC) with a LiChrospher 100 RP-18 5 μm column (Merck AG), using an elution buffer 100 mM Na acetate buffer pH 7/acetonitrile (95:5, v/v), a flow rate 1 mL/min and a Waters 2690 Alliance System (Waters Corp., Milford, MA, USA), with quantification at 235 nm as previously described.

  Eligibility

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • all patients under treatment with haemodialysis for ESRD for whom a treatment with temocillin was indicated according to the attending physician were eligible for the study.

Exclusion Criteria:

  • an age of less than 18 years
  • an estimated life-expectance of < 24 hours due to major co-morbid conditions
  • pregnancy
  • an IgE-mediated allergy to penicillins
  • patients not giving informed consent.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02285075


Locations
Belgium
AZ Sint-Jan Brugge Oostende AV
Brugge, Belgium, 8000
Louvain Drug Research Institute (LDRI)
Brussels, Belgium, 1020
Sponsors and Collaborators
AZ Sint-Jan AV
Paul Tulkens, Louvain drug research institute, belgium
Francoise Van Bambeke, Louvain drug research institute, belgium
Ana Miranda Bastos, Louvain drug research institute, belgium
Investigators
Principal Investigator: Stefaan J Vandecasteele, MD, PhD AZ Sint-Jan AV
  More Information

Publications:
Responsible Party: Vandecasteele Stefaan Johan, Stefaan Johan Vandecasteele, MD, PhD, AZ Sint-Jan AV
ClinicalTrials.gov Identifier: NCT02285075     History of Changes
Other Study ID Numbers: SVDC Temocillin 1
First Submitted: November 2, 2014
First Posted: November 6, 2014
Last Update Posted: January 5, 2016
Last Verified: January 2016

Keywords provided by Vandecasteele Stefaan Johan, AZ Sint-Jan AV:
temocillin
PD/PD
T>MIC

Additional relevant MeSH terms:
Infection
Renal Insufficiency
Bacterial Infections
Kidney Failure, Chronic
Gram-Negative Bacterial Infections
Kidney Diseases
Urologic Diseases
Renal Insufficiency, Chronic
Temocillin
Penicillins
Anti-Bacterial Agents
Anti-Infective Agents