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Evaluating Predictive Methods & Product Performance in Healthy Adults for Pediatric Patients, A Case Study: Furosemide

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ClinicalTrials.gov Identifier: NCT03093090
Recruitment Status : Withdrawn (Study never officially began)
First Posted : March 28, 2017
Last Update Posted : January 18, 2019
Sponsor:
Information provided by (Responsible Party):
Yale University

Brief Summary:
Poorly absorbed medications such as furosemide are common and recent experiments suggest that improvement in absorption can occur if these types of medications are consumed with liquids such as milk. The purpose of this study is to evaluate the absorption of furosemide in normal adults when taken with bottled water, milk (Parmalat™ Whole Milk), baby formula (Similac Pro-Advance™), or Ensure Plus™. These results will be used to make models that predict how these liquids will affect drug absorption in children, potentially providing ways to improve medication absorption in children.

Condition or disease Intervention/treatment Phase
Medication Absorption Dietary Supplement: Water Dietary Supplement: Parmalat™ Whole Milk Dietary Supplement: Similac Pro-Advance™ Dietary Supplement: Ensure Plus™ Drug: Furosemide 20 MG Phase 1

Detailed Description:

Low solubility drugs are common in the pharmacopeia and it has been estimated that more than 40% of new chemical entities developed by the pharmaceutical industry are practically insoluble in water. Exploratory in vitro studies by the CDER have recently demonstrated that the solubility, and thus potentially the bioavailability, of poorly soluble drugs may be highly enhanced when administered with milk (Parmalat™ Whole Milk) or baby formula (Similac Pro-Advance™).

While the reasons for variable bioavailability of furosemide are not well characterized, the effect of gastric pH, food and dosing liquids are commonly observed on the absorption of BCS Class IV drugs. Absorption variability is much greater in children due to developmental changes in factors such as gastric fluid, blood flow to the intestine, bile acid composition/secretion, intestinal surface area and drug metabolizing enzyme and transporter abundance. Therefore, it is critical to determine the physio-chemical physiological interactions for furosemide that can explain inter-subject and inter-dosing variability. An integrated in vitro, in silico and in vivo pharmacology approach to study the effect of dosing liquids on PK and PD of furosemide is novel. Quantitative understanding of factors affecting furosemide absorption will first be evaluated using in vitro tests such as solubility, dissolution and protein binding with the dosing liquids. The physiochemical information relevant to drug absorption and elimination will be curated from the literature to build the PBPK model. Such in vitro- in vivo extrapolation (IVIVE) linked PBPK modeling approach is crucial to better characterize furosemide's variable bioavailability. Another novel aspect of this study is that we will include renal metabolism of furosemide in the PBPK modeling. While plasma concentration will be critical in determining rate and extent of furosemide absorption, the renal elimination is the primary contributor to the PD response of furosemide as delivery of drug to the luminal surface of the renal tubule is required. PBPK modeling allows extrapolation of model to special population. For example, once the model is optimized and validated to predict effect of dosing liquids on adult PK of furosemide from in vitro data, this approach can be further extrapolated to children using pediatric gut physiological parameters. This novel approach will allow prediction of furosemide PK and PD in children without conducting a clinical study in this difficult to study population.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: A four-way randomized crossover PK study
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Evaluating Predictive Methods & Product Performance in Healthy Adults for Pediatric Patients, A Case Study: Furosemide
Estimated Study Start Date : December 31, 2018
Estimated Primary Completion Date : June 1, 2019
Estimated Study Completion Date : June 1, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Furosemide

Arm Intervention/treatment
Active Comparator: Water First
20mg furosemide administered PO with 6 oz of randomly-assigned study liquid
Dietary Supplement: Water
6 oz

Dietary Supplement: Parmalat™ Whole Milk
6 oz
Other Name: Milk

Dietary Supplement: Similac Pro-Advance™
6 oz
Other Name: baby formula

Dietary Supplement: Ensure Plus™
6 oz
Other Name: Ensure

Drug: Furosemide 20 MG
Furosemide is a loop diuretic (water pill) that prevents your body from absorbing too much salt.
Other Name: Lasix

Active Comparator: Milk First
Parmalat™ Whole Milk 20mg furosemide administered PO with 6 oz of randomly-assigned study liquid
Dietary Supplement: Water
6 oz

Dietary Supplement: Parmalat™ Whole Milk
6 oz
Other Name: Milk

Dietary Supplement: Similac Pro-Advance™
6 oz
Other Name: baby formula

Dietary Supplement: Ensure Plus™
6 oz
Other Name: Ensure

Drug: Furosemide 20 MG
Furosemide is a loop diuretic (water pill) that prevents your body from absorbing too much salt.
Other Name: Lasix

Active Comparator: Baby formula first
Similac Pro-Advance™ 20mg furosemide administered PO with 6 oz of randomly-assigned study liquid
Dietary Supplement: Water
6 oz

Dietary Supplement: Parmalat™ Whole Milk
6 oz
Other Name: Milk

Dietary Supplement: Similac Pro-Advance™
6 oz
Other Name: baby formula

Dietary Supplement: Ensure Plus™
6 oz
Other Name: Ensure

Drug: Furosemide 20 MG
Furosemide is a loop diuretic (water pill) that prevents your body from absorbing too much salt.
Other Name: Lasix

Active Comparator: Ensure Plus first
Ensure Plus™ 20mg furosemide administered PO with 6 oz of randomly-assigned study liquid
Dietary Supplement: Water
6 oz

Dietary Supplement: Parmalat™ Whole Milk
6 oz
Other Name: Milk

Dietary Supplement: Similac Pro-Advance™
6 oz
Other Name: baby formula

Dietary Supplement: Ensure Plus™
6 oz
Other Name: Ensure

Drug: Furosemide 20 MG
Furosemide is a loop diuretic (water pill) that prevents your body from absorbing too much salt.
Other Name: Lasix




Primary Outcome Measures :
  1. area under the plasma concentration curve [ Time Frame: 4 weeks ]
    The primary analysis will test for overall differences in bioavailability (area under the plasma concentration curve) of furosemide between different liquids. This will be accomplished using a repeated measures ANOVA, or if the distribution is not normally distributed a Wilcoxon-matched pairs sign-rank test.


Secondary Outcome Measures :
  1. differences in the peak plasma concentration in furosemide (C-max) [ Time Frame: 4 weeks ]
    Cmax is the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administrated and before the administration of a second dose. It is a standard measurement in pharmacokinetics. Cmax is the opposite of Cmin, which is the minimum (or trough) concentration that a drug achieves after dosing.

  2. total urinary sodium output [ Time Frame: 4 weeks ]
    collected via urine this is a standard metric of diuretic response



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age 18-40
  • 4 females and 4 males will be recruited
  • Free from known significant chronic medical illness (i.e., hypertension, diabetes, atherosclerosis, chronic kidney disease, liver disease, lupus, taking medications with known interactions with furosemide, a history of syncope/falls, or any acute illness, such as influenza, gastroenteritis, dehydration, electrolyte imbalance, or thrombosis risks).
  • Systolic Blood Pressure ≥90 mmHg at Screening Visit

Exclusion Criteria:

  • Inability to read English or give informed consent
  • Recent hospitalization within 6 months
  • Pregnant or lactating
  • Allergy or intolerance to furosemide
  • Allergy or intolerance to milk, milk products or soy
  • Inability to return for 4 consecutive weekly overnight visits at the study site
  • Female subjects with low, or borderline low blood pressure, will be evaluated carefully prior to enrollment, to ensure the safety of all subjects involved in the research study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03093090


Locations
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United States, Connecticut
Yale University
New Haven, Connecticut, United States, 06510
Sponsors and Collaborators
Yale University
Investigators
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Principal Investigator: Jeffrey Testani, MD Yale School of Medicine

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Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT03093090     History of Changes
Other Study ID Numbers: 2000020010
First Posted: March 28, 2017    Key Record Dates
Last Update Posted: January 18, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Yale University:
furosemide
Additional relevant MeSH terms:
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Furosemide
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Sodium Potassium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action