Clinical trial NCT02285075: Temocillin Pharmacokinetic in Hemodialysis
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?
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Gram-Negative Bacterial Infections
Renal Failure Chronic Requiring Hemodialysis
Keywords: temocillin
PD/PD
T>MIC
Lead sponsor: AZ Sint-Jan AV
Sponsor class: OTHER
Collaborators: name: Paul Tulkens, Louvain drug research institute, belgium
name: Francoise Van Bambeke, Louvain drug research institute, belgium
name: Ana Miranda Bastos, Louvain drug research institute, belgium
First posted: 2014-11-06
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: % of the dosing interval time above an MIC of 8 and 16 mg/L (% T>MIC 8 or 16 mg/L)
timeFrame: two to ten days
Secondary outcomes:
measure: Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis
timeFrame: two to ten days
measure: Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis
timeFrame: two to ten days
measure: Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis
timeFrame: two to ten days
measure: Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis
timeFrame: two to ten days
measure: Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis
timeFrame: two to ten days
measure: Determine basic pharmacokinetic parameters of temocillin in intermittent haemodialysis
timeFrame: two to ten days
Other outcomes:
Locations:
city: Brugge
country: Belgium
facility: AZ Sint-Jan Brugge Oostende AV
city: Brussels
country: Belgium
facility: Louvain Drug Research Institute (LDRI)
Study officials:
affiliation: AZ Sint-Jan AV
name: Stefaan J Vandecasteele, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.