Temocillin Pharmacokinetic in Hemodialysis

Gram-Negative Bacterial Infections Clinical Trial

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?

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02285075
• Other study ID #: SVDC Temocillin 1
• Status: Completed
• Phase: Phase 4
• First received: November 2, 2014
• Last updated: January 3, 2016
• Start date: June 2011
• Est. completion date: December 2014

Study information

• Verified date: January 2016
• Source: AZ Sint-Jan AV
• Contact: n/a
• Is FDA regulated: No
• Health authority: Belgium: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Bacterial Infections
• Gram-Negative Bacterial Infections
• Kidney Failure, Chronic
• Renal Failure Chronic Requiring Hemodialysis

Intervention

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).

Locations

Country	Name	City	State
Belgium	AZ Sint-Jan Brugge Oostende AV	Brugge
Belgium	Louvain Drug Research Institute (LDRI)	Brussels

Sponsors (4)

Lead Sponsor	Collaborator
AZ Sint-Jan AV	Ana Miranda Bastos, Louvain drug research institute, belgium, Francoise Van Bambeke, Louvain drug research institute, belgium, Paul Tulkens, Louvain drug research institute, belgium

Country where clinical trial is conducted

Belgium, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	% of the dosing interval time above an MIC of 8 and 16 mg/L (% T>MIC 8 or 16 mg/L)	Is T > MIC 8 and 16 mg/ML > 40 or 60 %	two to ten days	No
Secondary	Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis	Vd (volume of distribution)	two to ten days	No
Secondary	Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis	T1/2 (serum half life, on and of dialysis)	two to ten days	No
Secondary	Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis	Temocillin clearance (renal and non-renal)	two to ten days	No
Secondary	Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis	Temocillin reduction rate	two to ten days	No
Secondary	Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis	temocillin removal rate	two to ten days	No
Secondary	Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis	temocillin protein binding	two to ten days	No