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| ID | Type | Description | Link |
|---|---|---|---|
| 2013-001063-23 | EudraCT Number |
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Furosemide is a diuretic drug, used in the treatment of oedematous states associated with cardiac, renal, and hepatic disorder, and may be effective in patients unresponsive to thiazide diuretics. Furosemide is also used in the treatment of hypertension.
Absorption of furosemide from the gastrointestinal tract is fairly rapid; bioavailability is 60-70%, but variable and not predictable, with large intra- and inter-individual variability, and are influenced by dosage form, underlying diseases, and by the presence of food after oral administration. Data from animal model show that furosemide administered into the stomach is more rapidly absorbed than if is administered into the small intestine.
To increase the residency of furosemide in the stomach after oral administration, a gastroretentive dosage form (GRDF) of furosemide has been developed. In the current study, the new formulation (30mg furosemide coated tablet) will be tested in healthy male subjects. Absorption will be characterised by an effective and safe imaging technique - Magnetic Marker Monitoring (MMM), based on Fe3O4 added to the drug product to generate magnetic signal that can be used for up to 12 h after furosemide administration to localize the medication in the gastrointestinal tract. Fe3O4 is frequently used as colouring pigment in medicinal products. It does not exhibit own pharmacodynamic activity and is considered as an inactive ingredient.
In the current study, GRDF formulation of furosemide will be evaluated for: gastric residence as well as pharmacokinetic and pharmacodynamic characteristics under fasting and fed conditions. As part of the study, the subjects will be hospitalized for 1 day during each drug administration. The duration of the stay will depend on the intestinal behaviour of the investigational product.
Furosemide is a diuretic drug, widely used in the treatment of oedematous states associated with cardiac, renal, and hepatic disorder, and may be effective in patients unresponsive to thiazide diuretics. Furosemide is also used in the treatment of hypertension.
Absorption of furosemide from the gastrointestinal tract is fairly rapid. Bioavailability is reported as 60-70%, but is variable and not predictable. The rate and extent of absorption show a large intra- and inter-individual variability and are influenced by dosage form, underlying diseases, and by the presence of food after oral administration. Results obtained with an animal model indicate that furosemide administered into the stomach is more rapidly absorbed than if is is administered into the small intestine.
To increase the residency of furosemide in the stomach after oral administration, a gastroretentive dosage form (GRDF) of furosemide has been developed. In this study, the new formulation(30mg furosemide coated tablet) will be tested in healthy male subjects. Absorption will be characterised by imaging technique - Magnetic Marker Monitoring (MMM), which is the most effective and safe imaging technique currently available. MMM is based on a iron-III-oxide (Fe3O4) added to the drug product to generate magnetic signal that can be used to localize the administered medication in the gastrointestinal tract.
Fe3O4 is frequently used as colouring pigment in medicinal products. It does not exhibit own pharmacodynamic activity and thus, it is considered as clinically inactive ingredient. Fe3O4 exhibits a dipole moment and thus, after magnetisation of solid oral dosage forms containing homogenously distributed Fe3O4, the product generates a magnetic signal, which can be used for localisation of the dosage form in the gastrointestinal tract by Magnetic Marker Monitoring technique.
The aim of the current study is to evaluate the GRDF formulation of furosemide for: gastric residence, pharmacokinetic and pharmacodynamic characteristics under fasting and fed conditions. As part of the study, the subjects will be hospitalized for 1 day during each drug administration (i.e. a total of two days). The duration of the stay will depend on the intestinal behaviour of the investigational product. The MMM monitoring be performed for up to 12 h after furosemide administration. For pharmacokinetic determinations, liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) will be used to analyze furosemide in plasma.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| GRDF furosemide fasting conditions | Experimental | Subjects will be tested under fasting conditions after administration of GRDF Furosemide. |
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| GRDF furosemide fed conditions | Experimental | Subjects will be tested under fed conditions after administration of GRDF Furosemide. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| GRDF furosemide | Drug | The GRDF furosemide tablet contains Fe3O4, which serves as an inactive magnetic marker to allow monitoring of the tablet transit through the gastrointestinal tract, using the MMM imaging technique. |
| Measure | Description | Time Frame |
|---|---|---|
| Residency time of GRDF furosemide in the gastrointestinal tract, evaluated with MMM technique, under fasted and fed conditions. | Residency time of GRDF furosemide in the gastrointestinal track will be monitored using the non-invasive MMM technique under fasted and fed conditions. Measurements will start after each administration and last until 2 hours after gastric emptying indicated by the MMM measurement, but not longer than 12 h post administration. Each observation interval for each subject will last for a minimum of 10 min followed by a break of maximum 20 min. For meal intake, a break of the MMM measuring of 30 minutes will be performed. Anatomical localisation within the measuring sequences will be listed for each subject and treatment Statistical evaluation of gastric emptying time will include: arithmetic means, medians, minimum , maximum, standard deviation. GRDF=Gastro retentive dosage formulation | every 30 min for up to 12 h after drug administration; maximal observation time 12 h |
| Measure | Description | Time Frame |
|---|---|---|
| Cmax of GRDF furosemide under fasted conditions | Characterization of the pharmacokinetic (PK) properties of GRDF furosemide, with special focus on the absorption phase of furosemide. Compare results during fasted and fed state. Blood samples for the determination of furosemide concentration will be taken at pre-dose (within 1 h prior to administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after administration. LC-MS/MS will be used to analyze furosemide in plasma. Cmax = maximum concentration in plasma; GRDF=Gastro retentive dosage formulation |
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Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Frank Donath, MD | SocraTec R&D GmbH, Clinical Pharmacology Unit | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| SocraTec R&D GmbH Clinical Pharmacology Unit | Berlin | 10578 | Germany |
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| pre-dose (within 1 h prior to drug administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after drug administration. |
| Cmax of GRDF furosemide under fed conditions | Characterization of the pharmacokinetic (PK) properties of GRDF furosemide, with special focus on the absorption phase of furosemide. Compare results during fasted and fed state. Blood samples for the determination of furosemide concentration will be taken at pre-dose (within 1 h prior to administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after administration. LC-MS/MS will be used to analyze furosemide in plasma. Cmax = maximum concentration in plasma; GRDF=Gastro retentive dosage formulation | pre-dose (within 1 h prior to drug administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after drug administration. |
| tmax of GRDF furosemide under fasted conditions | Characterization of the pharmacokinetic (PK) properties of GRDF furosemide, with special focus on the absorption phase of furosemide. Compare results during fasted and fed state. Blood samples for the determination of furosemide concentration will be taken at pre-dose (within 1 h prior to administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after administration. LC-MS/MS will be used to analyze furosemide in plasma. tmax = time to reach maximum concentration in plasma; GRDF=Gastro retentive dosage formulation | pre-dose (within 1 h prior to drug administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after drug administration. |
| tmax of GRDF furosemide under fed conditions | Characterization of the pharmacokinetic (PK) properties of GRDF furosemide, with special focus on the absorption phase of furosemide. Compare results during fasted and fed state. Blood samples for the determination of furosemide concentration will be taken at pre-dose (within 1 h prior to administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after administration. LC-MS/MS will be used to analyze furosemide in plasma. tmax = time to reach maximum concentration in plasma; GRDF=Gastro retentive dosage formulation | pre-dose (within 1 h prior to drug administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after drug administration. |
| t1/2 of GRDF furosemide under fasted conditions | Characterization of the pharmacokinetic (PK) properties of GRDF furosemide, with special focus on the absorption phase of furosemide. Compare results during fasted and fed state. Blood samples for the determination of furosemide concentration will be taken at pre-dose (within 1 h prior to administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after administration. LC-MS/MS will be used to analyze furosemide in plasma. t1/2 = apparent terminal elimination half-life; GRDF=Gastro retentive dosage formulation | pre-dose (within 1 h prior to drug administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after drug administration. |
| t1/2 of GRDF furosemide under fed conditions | Characterization of the pharmacokinetic (PK) properties of GRDF furosemide, with special focus on the absorption phase of furosemide. Compare results during fasted and fed state. Blood samples for the determination of furosemide concentration will be taken at pre-dose (within 1 h prior to administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after administration. LC-MS/MS will be used to analyze furosemide in plasma. t1/2 = apparent terminal elimination half-life; GRDF=Gastro retentive dosage formulation | pre-dose (within 1 h prior to drug administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after drug administration. |
| AUC0-tlast of GRDF furosemide under fasted conditions | Characterization of the pharmacokinetic (PK) properties of GRDF furosemide, with special focus on the absorption phase of furosemide. Compare results during fasted and fed state. Blood samples for the determination of furosemide concentration will be taken at pre-dose (within 1 h prior to administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after administration. LC-MS/MS will be used to analyze furosemide in plasma. AUC0 = area under the plasma concentration vs. time curve from dosing time to the last measurement time point with a concentration value above the lower limit of quantitation, calculated by means of the linear up/log down method (linear trapezoidal rule for increases in concentration/logarithmic trapezoidal rule for decreases in concentrations; GRDF=Gastro retentive dosage formulation | pre-dose (within 1 h prior to drug administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after drug administration. |
| AUC0-tlast of GRDF furosemide under fed conditions | Characterization of the pharmacokinetic (PK) properties of GRDF furosemide, with special focus on the absorption phase of furosemide. Compare results during fasted and fed state. Blood samples for the determination of furosemide concentration will be taken at pre-dose (within 1 h prior to administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after administration. LC-MS/MS will be used to analyze furosemide in plasma. AUC0-tlast = area under the plasma concentration vs. time curve from dosing time to the last measurement time point with a concentration value above the lower limit of quantitation, calculated by means of the linear up/log down method (linear trapezoidal rule for increases in concentration/logarithmic trapezoidal rule for decreases in concentrations; GRDF=Gastro retentive dosage formulation | pre-dose (within 1 h prior to drug administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after drug administration. |
| AUC 0-infinity of GRDF furosemide under fasted conditions | Characterization of the pharmacokinetic (PK) properties of GRDF furosemide, with special focus on the absorption phase of furosemide. Compare results during fasted and fed state. Blood samples for the determination of furosemide concentration will be taken at pre-dose (within 1 h prior to administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after administration. LC-MS/MS will be used to analyze furosemide in plasma. AUC0-infinity = AUC0-tlast + AUCexpol; GRDF=Gastro retentive dosage formulation | pre-dose (within 1 h prior to drug administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after drug administration. |
| AUC 0-infinity of GRDF furosemide under fed conditions | Characterization of the pharmacokinetic (PK) properties of GRDF furosemide, with special focus on the absorption phase of furosemide. Compare results during fasted and fed state. Blood samples for the determination of furosemide concentration will be taken at pre-dose (within 1 h prior to administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after administration. LC-MS/MS will be used to analyze furosemide in plasma. AUC0-infinity = AUC0-tlast + AUCexpol; GRDF=Gastro retentive dosage formulation | pre-dose (within 1 h prior to drug administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after drug administration. |
| AUCextrapol of GRDF furosemide under fasted conditions | Characterization of the pharmacokinetic (PK) properties of GRDF furosemide, with special focus on the absorption phase of furosemide. Compare results during fasted and fed state. Blood samples for the determination of furosemide concentration will be taken at pre-dose (within 1 h prior to administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after administration. LC-MS/MS will be used to analyze furosemide in plasma. AUCextrapol = AUCextrapolated = Clast/lamda; lamda = apparent terminal elimination rate constant determined by log-linear regression; GRDF=Gastro retentive dosage formulation | pre-dose (within 1 h prior to drug administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after drug administration. |
| AUCextrapol of GRDF furosemide under fed conditions | Characterization of the pharmacokinetic (PK) properties of GRDF furosemide, with special focus on the absorption phase of furosemide. Compare results during fasted and fed state. Blood samples for the determination of furosemide concentration will be taken at pre-dose (within 1 h prior to administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after administration. LC-MS/MS will be used to analyze furosemide in plasma. AUCextrapol = AUCextrapolated = Clast/lamda; lamda = apparent terminal elimination rate constant determined by log-linear regression; GRDF=Gastro retentive dosage formulation | pre-dose (within 1 h prior to drug administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after drug administration. |
| CL_f of GRDF furosemide under fasted conditions | Characterization of the pharmacodynamic properties of GRDF furosemide, with special focus on the absorption phase of furosemide. Compare results during fasted and fed state. Blood samples for the determination of furosemide concentration will be taken at pre-dose (within 1 h prior to administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after administration. LC-MS/MS will be used to analyze furosemide in plasma. CL_f = apparent total body clearance of furosemide: dose / AUC0-∞; GRDF=Gastro retentive dosage formulation | pre-dose (within 1 h prior to drug administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after drug administration. |
| CL_f of GRDF furosemide under fed conditions | Characterization of the pharmacodynamic properties of GRDF furosemide, with special focus on the absorption phase of furosemide. Compare results during fasted and fed state. Blood samples for the determination of furosemide concentration will be taken at pre-dose (within 1 h prior to administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after administration. LC-MS/MS will be used to analyze furosemide in plasma. CL_f = apparent total body clearance of furosemide: dose / AUC0-∞; GRDF=Gastro retentive dosage formulation | pre-dose (within 1 h prior to drug administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after drug administration. |
| Vdz of GRDF furosemide under fasted conditions | Characterization of the pharmacodynamic properties of GRDF furosemide, with special focus on the absorption phase of furosemide. Compare results during fasted and fed state. Blood samples for the determination of furosemide concentration will be taken at pre-dose (within 1 h prior to administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after administration. LC-MS/MS will be used to analyze furosemide in plasma. Vdz = apparent volume of distribution of furosemide: dose / (AUC0-∞ x λ); GRDF=Gastro retentive dosage formulation; λ=apparent terminal elimination rate constant determined by log-linear regression | pre-dose (within 1 h prior to drug administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after drug administration. |
| Vdz of GRDF furosemide under fed conditions | Characterization of the pharmacodynamic properties of GRDF furosemide, with special focus on the absorption phase of furosemide. Compare results during fasted and fed state. Blood samples for the determination of furosemide concentration will be taken at pre-dose (within 1 h prior to administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after administration. LC-MS/MS will be used to analyze furosemide in plasma. Vdz = apparent volume of distribution of furosemide: dose / (AUC0-∞ x λ); GRDF=Gastro retentive dosage formulation; λ=apparent terminal elimination rate constant determined by log-linear regression | pre-dose (within 1 h prior to drug administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, and 24 h after drug administration. |
| Sodium excretion over time under fasted conditions | Sodium in urine will be measured for each time interval and total sampling time. Urine will be collected and sampled during the following sample intervals: pre-dose (within 1 hour prior to administration), 0-2h, 2-4h, 4-8h, and 8-12h after administration. | pre-dose (within 1 hour prior to administration), 0-2h, 2-4h, 4-8h, and 8-12h after administration. |
| Sodium excretion over time under fed conditions | Sodium in urine will be measured for each time interval and total sampling time. Urine will be collected and sampled during the following sample intervals: pre-dose (within 1 hour prior to administration), 0-2h, 2-4h, 4-8h, and 8-12h after administration. | pre-dose (within 1 hour prior to administration), 0-2h, 2-4h, 4-8h, and 8-12h after administration. |
| Urine excretion over time under fasted conditions | Urine volume will be measured for each time interval and total sampling time. Urine will be collected and sampled during the following sample intervals: pre-dose (within 1 hour prior to administration), 0-2h, 2-4h, 4-8h, and 8-12h after administration. | pre-dose (within 1 hour prior to administration), 0-2h, 2-4h, 4-8h, and 8-12h after administration. |
| Urine excretion over time under fed conditions | Urine volume will be measured for each time interval and total sampling time. Urine will be collected and sampled during the following sample intervals: pre-dose (within 1 hour prior to administration), 0-2h, 2-4h, 4-8h, and 8-12h after administration. | pre-dose (within 1 hour prior to administration), 0-2h, 2-4h, 4-8h, and 8-12h after administration. |
| ID | Term |
|---|---|
| D004487 | Edema |
| ID | Term |
|---|---|
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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