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?

Sponsors

Lead Sponsor: AZ Sint-Jan AV

Collaborator: Paul Tulkens, Louvain drug research institute, belgium
Francoise Van Bambeke, Louvain drug research institute, belgium
Ana Miranda Bastos, Louvain drug research institute, belgium

Source AZ Sint-Jan AV
Brief Summary

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.

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.

Overall Status Completed
Start Date 2011-06-01
Completion Date 2014-12-01
Primary Completion Date 2014-12-01
Phase Phase 4
Study Type Interventional
Primary Outcome
Measure Time Frame
% of the dosing interval time above an MIC of 8 and 16 mg/L (% T>MIC 8 or 16 mg/L) two to ten days
Secondary Outcome
Measure Time Frame
Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis two to ten days
Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis two to ten days
Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis two to ten days
Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis two to ten days
Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis two to ten days
Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis two to ten days
Enrollment 16
Condition
Intervention

Intervention Type: Drug

Intervention Name: temocillin PK/PD in haemodialysis

Description: 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).

Arm Group Label: temocillin PK/PD in haemodialysis

Eligibility

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.

Gender:

All

Minimum Age:

18 Years

Maximum Age:

N/A

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
Stefaan J Vandecasteele, MD, PhD Principal Investigator AZ Sint-Jan AV
Location
Facility:
AZ Sint-Jan Brugge Oostende AV | Brugge, 8000, Belgium
Louvain Drug Research Institute (LDRI) | Brussels, 1020, Belgium
Location Countries

Belgium

Verification Date

2016-01-01

Responsible Party

Type: Principal Investigator

Investigator Affiliation: AZ Sint-Jan AV

Investigator Full Name: Vandecasteele Stefaan Johan

Investigator Title: Stefaan Johan Vandecasteele, MD, PhD

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Label: temocillin PK/PD in haemodialysis

Type: Other

Description: 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

Study Design Info

Allocation: N/A

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

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