Temocillin Pharmacokinetic in Hemodialysis

January 3, 2016 updated by: Vandecasteele Stefaan Johan, AZ Sint-Jan AV

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?

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.

Study Overview

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.

Study Type

Interventional

Enrollment (Actual)

16

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Brugge, Belgium, 8000
        • AZ Sint-Jan Brugge Oostende AV
      • Brussels, Belgium, 1020
        • Louvain Drug Research Institute (LDRI)

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
OTHER: 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
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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
% 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 %
two to ten days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis
Time Frame: two to ten days
Vd (volume of distribution)
two to ten days
Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis
Time Frame: two to ten days
T1/2 (serum half life, on and of dialysis)
two to ten days
Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis
Time Frame: two to ten days
Temocillin clearance (renal and non-renal)
two to ten days
Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis
Time Frame: two to ten days
Temocillin reduction rate
two to ten days
Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis
Time Frame: two to ten days
temocillin removal rate
two to ten days
Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis
Time Frame: two to ten days
temocillin protein binding
two to ten days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

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Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2011

Primary Completion (ACTUAL)

December 1, 2014

Study Completion (ACTUAL)

December 1, 2014

Study Registration Dates

First Submitted

November 2, 2014

First Submitted That Met QC Criteria

November 5, 2014

First Posted (ESTIMATE)

November 6, 2014

Study Record Updates

Last Update Posted (ESTIMATE)

January 5, 2016

Last Update Submitted That Met QC Criteria

January 3, 2016

Last Verified

January 1, 2016

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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