- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02285075
Temocillin Pharmacokinetic in Hemodialysis
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?
Study Overview
Status
Intervention / Treatment
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
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
-
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Brugge, Belgium, 8000
- AZ Sint-Jan Brugge Oostende AV
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Brussels, Belgium, 1020
- Louvain Drug Research Institute (LDRI)
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
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
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
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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).
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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
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Is T > MIC 8 and 16 mg/ML > 40 or 60 %
|
two to ten days
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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
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Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis
Time Frame: two to ten days
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Temocillin clearance (renal and non-renal)
|
two to ten days
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Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis
Time Frame: two to ten days
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Temocillin reduction rate
|
two to ten days
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Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis
Time Frame: two to ten days
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temocillin removal rate
|
two to ten days
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Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis
Time Frame: two to ten days
|
temocillin protein binding
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two to ten days
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Stefaan J Vandecasteele, MD, PhD, AZ Sint-Jan AV
Publications and helpful links
General Publications
- Miranda Bastos AC, Vandecasteele SJ, Tulkens PM, Spinewine A, Van Bambeke F. Development and validation of a high performance liquid chromatography assay for the determination of temocillin in serum of haemodialysis patients. J Pharm Biomed Anal. 2014 Mar;90:192-7. doi: 10.1016/j.jpba.2013.12.002. Epub 2013 Dec 12.
- Miranda Bastos AC, Vandecasteele SJ, Spinewine A, Tulkens PM, Van Bambeke F. Temocillin dosing in haemodialysis patients based on population pharmacokinetics of total and unbound concentrations and Monte Carlo simulations. J Antimicrob Chemother. 2018 Jun 1;73(6):1630-1638. doi: 10.1093/jac/dky078.
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- SVDC Temocillin 1
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