Primary objective: To study the pharmacokinetics of gentamicin, tobramycin, vancomycin and ciprofloxacin in morbidly obese patients and compare with normal weight patients. Secondary objectives: To assess the influence of covariates (such as TBW,…
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Source
Brief title
Condition
- Bacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint is clearance (Cl) of gentamicin, tobramycin, vancomycin or
ciprofloxacin in obese participants versus normal weight participants. Other
primary endpoints are volume of distribution (Vd) for all four drugs and oral
bioavailability (F) for ciprofloxacin in obese participants versus normal
weight participants.
Secondary outcome
Influence of covariates (total bodyweight, lean bodyweight, gender, length,
age, creatinine, metabolomic profile, history/duration of obesity (estimation
of number of years the patient fulfils definition of morbid obesity), GFR) on
primary parameters of interest (i.e. clearance and volume of distribution). The
covariate *metabolomic profile* means that we want to investigate the influence
of the metabolism of several endogen components on the different PK-parameters.
Other study parameters:
GFR measured using creatinine concentration in urine collected over 24 hours in
morbidly obese participants.
Background summary
Infectious diseases are a major public health threat. In general, adequate
treatment with antibiotics (i.e. an effective dose) is essential for the
survival of patients with infectious diseases. For many antibiotics, available
evidence on how to adjust the dose in (morbid) obesity in clinical practice is
insufficient, such despite the fact that both the prevalence of (morbid)
obesity (BMI>(40/)30 kg/m2) and the bodyweights itself are increasing
worldwide. Obesity and particularly morbid obesity are known to influence
different pharmacokinetic parameters such as clearance and volume of
distribution, even though exact quantification is still warranted for many
drugs.
For severe life-threatening infections, aminoglycosides and vancomycin are
important antibiotics. Fluoroquinolones (especially ciprofloxacin) play an
important role in the treatment of moderate to severe infections, ranging from
soft tissue infections to infections of the pulmonary, gastrointestinal or
urogenital tract.
For aminoglycosides and vancomycin there is a distinct relation between serum
concentrations and both efficacy and toxicity (e.g. nephrotoxicity). Timely
attainment of target concentrations is of utmost importance and has been
recognized as key element in the surviving sepsis campaign. In daily clinical
practice, dosing in morbidly obese patients is still based on dose guidelines
for normal weight patients after which Therapeutic Drug Monitoring (TDM) is
applied to adjust the subsequent doses. Using this approach, there may be a
substantial delay in time to attain target concentrations known to lead to
optimal effect and prevent toxicity. This inability to upfront predict the
adequate dose puts the morbidly obese patients at increased risk of failure of
therapy or toxicity. This is also the case for fluoroquinolones, where in
general practice TDM is not routinely performed and (morbidly) obese patients
are at risk for failure of therapy when serum concentrations are too low. For
these reasons, evidence on the pharmacokinetics of aminoglycosides, vancomycin
and ciprofloxacin in (morbidly) obese patients is highly warranted in order to
provide a basis for a dosing guideline for this special patient population.
Currently, dosing guidelines for these antibiotics are lacking specific dose
adaptations for (morbidly) obese patients, since there is a paucity of data in
available literature on (the pharmacokinetics) these antibiotics that can
actually be used to guide dosing. This is due to several reasons, with among
others are the application of now uncommon dosing frequencies and target
concentrations of these antibiotics (i.e. studies on three times daily dosing
of aminoglycosides with only 8h sampling schemes, whereas currently once daily
dosing with 24 h sampling is applied), outdated definitions of obesity (i.e.
drugs have been studied in nowadays only mildly obese patients), inadequate
characterization of the pharmacokinetics (i.e. due to limited number of samples
per individual (use of TDM data)) and/or other suboptimal methodology (i.e.
unavailability of non-obese controls)). For ciprofloxacin, there is one study
available on intravenous dosing without information on oral absorption while
sampling was done over 6h instead of 8h making extrapolation to dosing
guidelines difficult. In conclusion, there is a clear lack in the available
literature to design dosing guidelines that can be expected to result in
predictable drug concentrations that correlate with optimal efficacy and safety
in this special patient population in clinical practice.
Study objective
Primary objective:
To study the pharmacokinetics of gentamicin, tobramycin, vancomycin and
ciprofloxacin in morbidly obese patients and compare with normal weight
patients.
Secondary objectives:
To assess the influence of covariates (such as TBW, LBW, serum creatinine,
metabolomics and Glomerular Filtration Rate (GFR)) on the pharmacokinetics of
gentamicin, tobramycin, vancomycin and ciprofloxacin. To develop dosing
recommendations for gentamicin, tobramycin, vancomycin and ciprofloxacin in
(morbidly) obese individuals.
Study design
This is a prospective intervention study which will be performed in (morbidly)
obese patients undergoing weight-loss surgery. A control group consisting of
normal weight patients will also be included. Patients will be allocated to
receive one dosage of one of the following drugs:
- gentamicin IV
- tobramycin IV
- vancomycin IV
- ciprofloxacin PO, followed after 3 hours by ciprofloxacin IV for healthy
volunteers. Obese subjects receive ciprofloxacin PO or IV.
Up to 24 hours post-infusion (or 48 hours in patients receiving vancomycin and
12 hours in patients receiving ciprofloxacin) blood samples will be drawn to
calculate different pharmacokinetic parameters.
Intervention
In this study, the intervention consists of the administration of one dose of
the investigational drug (gentamicin, tobramycin, vancomycin or ciprofloxacin).
- 5 mg/kg LBW (for obese participants, n = 20) or 5 mg/kg TBW (for healthy
volunteers, n = 8) gentamicin IV (maximum of 500 mg, rounded up on the nearest
multiple of 40 mg)
- 5 mg/kgLBW (for obese participants, n = 20) or 5 mg/kg TBW (for healthy
volunteers, n = 8) tobramycin IV (maximum of 500 mg, rounded up on the nearest
multiple of 40 mg)
- 12,5 mg/kg TBW (for obese participants, max 2500 mg) or 1000 mg (for healthy
volunteers) vancomycin IV
- Ciprofloxacin; for healthy volunteers 500 mg PO followed after 3 hours by
ciprofloxacin 400 mg IV (n=8). For obese participants 500mg PO or
ciprofloxacin 400mg IV (n = 20)
LBW is calculated using the Janmahasatian method, which is considered most
accurate for calculating LBW.
Study burden and risks
This is a prospective, non-randomized PK clinical study in morbidly obese,
bariatric surgery patients and normal weight volunteers.
The main burden for study participants consists of a single administration of
gentamicin, tobramycin, vancomycin or ciprofloxacin (in which case two dosages
are administered, one oral and one IV). The main side-effects associated with
these drugs are nephro- or ototoxicity (aminoglycosides and vancomycin) or
allergic reactions. As for all antibiotics, possible side-effects are the
development of resistance and disturbance of the gut flora.The main side
effects of ciprofloxacin are nausea and diarrhea. Additional burden consist of
an indwelling venous catheter, 13-21 blood samples to be drawn from this
catheter (depending on allocation) and the collection of urine during 24 hours
post infusion. It is estimated that per participant 44 * 69 ml blood will be
drawn in total during the study.
Our research group has developed extensive experience with this kind of
research as within this infrastructure many PK studies have been executed over
the last 10 years. Concerning the drugs studied, there is ample experience with
these drugs in daily clinical practice. When administered according to the
local handbook on parenterals ('Handboek Parenteralia'), we know that the risks
associated with the different study drugs are minimalized. In case of an
allergic reaction to one of the study drugs, treatment will be started
according to the hospital*s protocol, resulting in a minimalized chance on
complications. In addition, we expect that side effects for a single dose of
ciprofloxacin will be mild, if they occur at all.
Koekoekslaan 1
Nieuwegein 3435 CM
NL
Koekoekslaan 1
Nieuwegein 3435 CM
NL
Listed location countries
Age
Inclusion criteria
Inclusion criteria for (morbidly) obese participants:
- Indication for bariatric surgery (i.e. BMI > 40 kg/m2 or BMI > 35 kg/m2 with additional risk factors). Bariatric surgery includes the following: laparoscopic gastric bypass surgery or laparoscopic sleeve gastrectomy. We will equally stratify subjects to 4 weight groups: 100-120 kg, 120-145 kg, 145-170 kg and >170 kg;
- Participants between 18 - 60 years old;
- ASA physical classification of II or III;
- Participant is able and willing to sign the Informed Consent before screening evaluations.;Inclusion criteria for controls (normal weight participants):
- BMI between 18 and 25 kg/m2;
- Participants between 18 - 55 years old;
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded from participation in this study:;- Known allergy to the administered drug;
- Recent use of the study drug (up to 7 days before administration of the study drug);
- Treatment with the concerning study drug up to 7 days before administration of the study drug.
- Pregnancy or breastfeeding. This is an exclusion criteria for bariatric surgery as well (participants are informed by their surgeon and bariatric nurse). Women of childbearing potential using contraception are allowed to participate in the study.;Specific exclusion criteria for participants receiving an aminoglycoside or vancomycin:
- Renal insufficiency identified by eGFR < 60 ml/min/1.73m2. A recent serum creatinine (measured in the previous year) has to be known to assess this criterion. When not available, the patient*s own general practioner or pharmacy can be contacted for a recent serum creatinine. This is only done with oral consent from the patient. If not available, then serum creatinine is measured before the study drug is administered (see study procedures) with priority);
- Participant who are treated with known nephro- or ototoxic drugs (immunosuppressants, antivirals, antineoplastic agents, ACE-inhibitors, lisdiuretics, aminoglycosides, vancomycin) up to 7 days before administration of the study drug. For NSAIDs, participants are not allowed to use a NSAID 24 hours before administration of the study drug (with the exception of meloxicam (72 hours), nabumeton (72 hours) or piroxicam 7 days). ;Specific exclusion criteria for participants receiving ciprofloxacin IV:;- Known liver disease identified by liver function tests: ASAT, ALAT, prothrombin time, *-GT, bilirubin, or alkaline phosphatase (ALP) (> 3 times upper limit of normal values)
- Known prolonged QT-interval or participants that use drugs that are known to prolong the QT-interval (based on the list published by CredibleMeds®, formerly known as AZCERT)
- Epilepsy
- Myasthenia gravis
- Porphyria cutanea tarda
- Psychoses in history
- Participants that use drugs that are known to be metabolized by CYP1A2 or CYP3A4;Additional exclusion criteria for participants receiving ciprofloxacin PO:;- Participants that use oral drugs that contain bivalent cations (calcium, magnesium, aluminum or iron), phosphate binders (sevelamer) or sucralphate, influence gastric emptying or antacids less than 6 hours before administration of ciprofloxacin.;For healthy volunteers a few extra prohibitions apply to participation (these are standard prohibitions employed in the CRCN):
- Water is allowed as desired except for one hour before and one hour after administration of study medication.
- From four hours after dosing until release of confinement, consumption of available beverages is free and meals are standardized in regard to consumption and time of administration.
- No history of alcohol or drugs abuse (up until one month before study drug administration).
- Subjects may not consume alcoholic beverages from 24 hours before until 48 hours after administration of study medication.
- Subjects may not use grapefruit containing food or juice, or St John*s worth, from 7 days before until the end of the study.
- Female subjects of childbearing potential without adequate contraception, e.g. hysterectomy, bilateral tubal ligation, (non-hormonal) intrauterine device, total abstinence, double barrier methods, or two years post-menopausal. They must agree to take precautions in order to prevent a pregnancy throughout the study period. Male subjects should also use contraceptive methods in order to avoid pregnancy of their partners during the study period.
- Subjects are to refrain from strenuous exercise of all types while at the clinical research centre and at the day prior to administration of study medication.
- Subjects are not allowed to lie down without permission from one hour before until 4 hours after dosing of oral ciprofloxacin because body position and posture may influence physiological characteristics such as dissolution and (the rate of) absorption of ciprofloxacin.
- Subjects are not allowed to smoke at the clinical research centre.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-004814-84-NL |
| CCMO | NL52260.100.16 |
| OMON | NL-OMON29597 |