To assess the effect of TIPS on drug metabolism of different drugs, metabolized by different metabolic pathways in patients with an elective TIPS placement using a cocktail approach, and to assess the effect of TIPS on bile acid metabolism.
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary study endpoint is the difference in area under the plasma concentration
versus time curve for each drug following the oral administration of the drug
cocktail two weeks before TIPS placement, a day after TIPS placement, and
twelve weeks after TIPS placement.
Secondary outcome
Secondary endpoints include the difference in the following pharmacokinetics
parameters: clearance, volume of distribution, absorption rate, mean residence
time and elimination half-life. In addition, we want to assess the effect of
TIPS placement on the postprandial levels of bile acids, glucose, insulin,
c-peptide, GLP-1, FGF19, C4 and glucagon by MMT.
Background summary
Liver cirrhosis is the end stage of chronic liver injury, and is associated
with portal hypertension. Transjugular Intrahepatic Portosystemic Shunt (TIPS)
is a highly effective intervention to reduce elevated portal pressure and
reduce complication rates of portal hypertension. Hepatic biotransformation of
endogenous toxins, hormones or the pharmacokinetics of drugs may be affected by
TIPS placement, but prospective controlled studies are lacking.
Study objective
To assess the effect of TIPS on drug metabolism of different drugs, metabolized
by different metabolic pathways in patients with an elective TIPS placement
using a cocktail approach, and to assess the effect of TIPS on bile acid
metabolism.
Study design
Open-label, single-dose crossover intervention study.
Intervention
This study consists of three interventions per patient. Patients will receive a
single oral administration of a drug cocktail two weeks before TIPS placement,
a day after TIPS placement, and twelve weeks after TIPS placement. The oral
drug cocktail consists of 50 mg caffeine, 5 mg warfarin, 20 mg omeprazole, 20
mg metoprolol and 0.015 mg/kg midazolam. In addition to the drug cocktail,
patients undergo a mixed meal tests (MMT), using Nutridrink compact, and
measurement of body expenditure and body composition.
Study burden and risks
Additionally to an admission for elective TIPS placement and observation
(standard of care), patients will undergo a screening visit, and two additional
10-hour hospital admissions for administration of the oral drug cocktail, MMT
and subsequent blood sampling. The second administration will take place during
the (standard of care) observation after TIPS placement.
Patients will visit the clinic two times (day 1 and 3) after each oral
administration for PK analysis and coagulation monitoring. One urine sample
will be taken to perform an urinary drug screening and for analysis of sodium
and potassium levels. A total of 64 blood samples will be drawn. During
screening visit this consists of 4 samples for monitoring of laboratory
parameters (n=3) and for pharmacogenetic analysis of liver enzymes (n=1).
During each admission for administration of the cocktail 20 samples will be
drawn for PK and metabolic analysis (bile acids and other postprandial markers)
via an intravenous catheter. A total volume of 306 mL blood will be obtained
for this study. Effects of TIPS placement on energy metabolism will be assessed
with indirect calorimetry and body composition.
This study will generate information regarding alterations in pharmacokinetics
due to TIPS and bile acid metabolism before and after TIPS placement and may
therefore be of future benefit for patients who undergo TIPS placement using
medication.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
1. Liver cirrhosis as documented by liver biopsy or elastography (e.g.
Fibroscan > 15 kPa) in combination with usual radiological and biochemical
signs.
2. Age > 18 years.
3. Elective indication for TIPS (recurrent tense ascites, recurrent/refractory
hepatic hydrothorax, or (recurrent) oesophageal or gastric bleeding treated
with endoscopic band ligation (EBL) or endoscopic injection sclerotherapy (EIS)
more than 2 weeks prior to screening.
4. Signed informed consent
Exclusion criteria
Absolute contraindications for TIPS placement
Child-Pugh score >= 10
MELD score > 20
Serum bilirubin 51 > µmol/L
INR > 1.7
Serum creatinine > 185 µmol/L
Active drug abuse or alcoholism
Overt neurologic disease
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL65505.018.18 |