Pharmacokinetic trial in patients, with a good general condition before standard abdominal surgery
Conditions
Interventions
Trade Name: Codeintropfen-CT
Product Name: Codeinphosphat-Hemihydrat
Pharmaceutical Form: Oral drops
INN or Proposed INN: CODEINE PHOSPHATE HEMIHYDRATED
Concentration unit: mg/g milligram(s)/gram
Conc
Sponsors
Universitätsklinikum Schleswig-Holstein, Campus Kiel
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients before elective visceral surgery including patient with Child A/B liver cirrhosis and/or compensated renal impairment (grade 1-2) without severe edema, ascites etc.. 2. Written informed consent obtained prior to study entry including informed consent for genetic research 3. Both genders (male and female) 4. Adults aged =18 to =65 years) yes F.1.3.1 Number of subjects for this age range 20
Exclusion criteria
Exclusion criteria: 1. Participation in a clinical trial involving the administration of medicines during the last 30 days or use of any other investigational or non-registered drug or vaccine during the study period or within 30 days preceding the first dose of study drugs 2. Blood, plasma or thrombocyte donation during the last 30 days prior to application of the test drugs. 3. Pregnancy or lactation period 4. Bradycardia, prolonged PQ-time, AV-block. 5. Raynaud’s syndrome 6. Short bowel syndrome, previous bariatric surgery, chronic inflammatory bowel disease (Crohn disease, ulcerative colitis), malabsorption, celiac disease, previous operative intestinal anastomoses such as Y-Roux as they may interfere with the PK of the study drug 7. Patients with any decompensated medical condition, cardiac failure, edema, active infection, sepsis, open wounds, necrosis, uncontrolled psychiatric disorder or psychosis. 8. Inability to walk, dementia, parenteral nutrition or nutrition over enteral feeding tube. 9. Change of the concomitant standard medication of the patients within the last two weeks unless allowed for the specific drug as detailed in the “Concominant Medication” section 3.4.2. 10. Active alcohol and/or drug addiction and/or active abusive use of medicaments. 11. Transplanted patients. 12. History of severe hypersensitivity reactions and anaphylaxis. 13. History of intolerance or allergic reactions to or contraindication for any of the IMPs. If intolerance, allergic reactions to or contraindication against one of the IMPs is known, enrolment is possible but application of the concerned substance must not be allowed in the affected individual and all siblings (e.g. allergy to sulphonamide prohibits specifically the application of torasemide) 14. Contraindication against MRI, e.g. pacemakers, cochlea implants, aneurysm clips, claustrophobia, allergy against gadolinum-containing contrast agents. If allergic reactions against gadolinum-containing contrast agents is known, enrolment is possible but the affected patient is excluded from MRI. 15. Inability or unwillingness to provide informed consent and to abide by the requirements of the study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: While visit 2;Main Objective: To establish a cohort of patients before routine visceral surgery. This cohort should serve as a patient cohort for the related healthy volunteer study in Tübingen, Germany (IKP243; EudraCT: 2011-002291-16). Functional pharmacokinetic phenotyping of major drug metabolism pathways (cytochrome P450 1A2, 2C9, 2D6, 3A4/5, and uridine glucuronosyl transferase 2B4/7) and drug transporter (OATP1B1) pathways. Functional measurement of liver metabolic function;Secondary Objective: Noninvasive functional characterization of liver, heart, and kidneys using MRI Detailed multi-scale modeling of individuals and personalized prediction of liver detoxification capacity based on biomarkers Sampling of biological material (serum, plasma, peripheral blood cells) Generation of hypotheses and identification and evaluation of (epi)genetic, genomic, transcriptomic, proteomic and metabolic biomarkers. ;Primary end point(s): Blood levels and clearance (dose/AUC) of midazolam, torasemide, codeine, pravastatin Endogenous CYP3A markers (urinary 6betaOH cortisol/cortisol ratio or plasma 4-OH cholesterol (CYP3A4/5)) Blood levels and clearance (dose/AUC) of caffeine, paraxanthine, 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 5-acetylamino-6-amino-3-methyluracil (AAMU) PK variables are: Area under plasma concentration versus time curve (AUC), oral clearance (CL/F), maximum plasma drug concentration (Cmax), terminal half-life (t½), time to reach Cmax (tmax) and oral volume of distribution (V/F) | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: while visit 2;Secondary end point(s): Plasma metabolite profiles and PK parameters (1-OH-midazolam, OH-torasemide (M1), carboxy-torasemide (M5), morphine, codeine-6-glucuronide, morphine-6-glucuronide, morphine-3-glucuronide, norcodeine, normorphine) Urinary levels of 1-OH-midazolam, codeine-3-glucuronide, codeine-6-glucuronide, morphine-6-glucuronide, morphine-3-glucuronide, norcodeine, normorphine, pravastatin, AFMU, AAMU Plasma and/or urinary metabolic ratios of parent compound versus the metabolites generated by the enzymes of interest (Table 5). Following selected secondary endpoints will be calculated per phenotyping probe: Pravastatin -Elimination rate constant of pravastatin as an indicator of hepatic OATP1B1 activity Codeine: -Renal excretion (Ae) of morphine as an indicator of CYP2D6 activity -Renal excretion (Ae) of codeine-glucuronides and morphine-glucuronides as indicators of UGT2B4 and -2B7 activity -Renal excretion (Ae) of norcodeine and normorphine as indicators of CYP2C8 and CYP3A4 activities Torasemide: -Metabolite formation clearances for torasemide as indicators of hepatic CYP2C9 activity 13C-caffeine test: -Urinary metabolite ratio of caffeine metabolites AAMU and AFMU as indicators of hepatic NAT2 activity -1,7-Dimethylxanthine (paraxanthine) over caffeine plasma metabolic ratios at 2 hours as an indicator of hepatic CYP1A2 activity Laborchemical parameters for liver and renal function Liver MRI (facultative): Cross-sectional area (S), maximum velocity (Vmax), Mean velocity (Vmean), and flow rate (Q) of portal and proper hepatic artery; liver volume (LV) Cardiac MRI (facultative): left / right ventricular end-diastolic volume (LVEDV, RVEDV), left / right ventricular end-systolic volume (LVESV, RVESV), left / right ventricular ejection fraction (LVEF, RVEF), left / right ventricular stroke volume (LVSV / RVSV) Body composition MRI (facultative): visceral adipose tissue, subcutaneous adipose tissue, | — |
Countries
Germany
Contacts
Public ContactKlinik für Allgemeine Chirurgie
Universitätsklinikum Schleswig-Holstein, Campus Kiel
Outcome results
None listed