Pharmacokinetics and Clinical Response of Tolvaptan in Neurocritical Care Patients

To assess the pharmacokinetic profile of tolvaptan in critically ill acute brain injury patients and to secondarily evaluate the clinical response and safety of tolvaptan in acute brain injured patients

Study Overview

• Status: Terminated
• Conditions: Brain Injury; Hyponatremia
• Intervention / Treatment: Drug: Tolvaptan

• Study Type: Observational
• Enrollment (Actual): 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Barnes-Jewish Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina Hospitals
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The population will be comprised of 30 acute brain injury patients in the ICU.

Description

Inclusion Criteria:

1. Acute brain injury patients in the ICU with hyponatremia (Na < 135 mmol/L) necessitating treatment in addition to fluid restriction per clinical judgement or patients at risk for worsening cerebral edema
2. Informed consent obtained from patient or authorized legal representative
3. Age ≥ 18 years

Exclusion Criteria:

1. Use of CYP3A4 inhibitors or inducers as medications, juices, or herbal supplements within 96 hours prior to the study period.
2. A positive urine or serum pregnancy test, or are currently breast-feeding
3. Patients with subarachnoid hemorrhage or in patients suspected to have cerebral salt wasting or any signs of volume depletion
4. Imminent death or brain death
5. Concomitant fungal infection
6. History of HIV
7. Concomitant administration of continuous infusion hypertonic saline, conivaptan or hypertonic saline bolus within 24 hours of study drug administration
8. Diuretic or mannitol administration within 6 hours
9. Serum creatinine ≥ 3.5 mg/dL
10. Diagnosis of cirrhosis or liver function tests > 2x the upper limit of normal

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Brain injured patients with hyponatremia; Patients with acute brain injury who develop hyponatremia and are administered tolvaptan via the nasogastric tube, deemed necessary by the primary medical team.	Drug: Tolvaptan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum observed plasma concentration (Cmax) and time to maximum observed plasma concentration (Tmax) of tolvaptan over 36 hours post-dose	Cmax will be derived from plasma concentrations versus time using a validated LS/MS/MS assay is sodium heparinized plasma. The tolvaptan assay has a range of 1.00 - 200 mg/mL. Blood samples will be collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 30 and 36 hours after the dose of tolvaptan is administered. The first 15 patients will receive single dose 15mg of tolvaptan via a gastric tube and if determined not bioequivalent and no clinical response to oral administration and safe to administer, then last 15 patients will receive 30mg single dose via a gastric tube.	Over 36 hours from drug administration
The elimination rate constant (ke) of tolvaptan over 36 hours post-dose	Ke derived from plasma concentrations versus time using a validated LS/MS/MS assay is sodium heparinized plasma. The tolvaptan assay has a range of 1.00 - 200 mg/mL. Blood samples will be collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 30 and 36 hours after the dose of tolvaptan is administered. The first 15 patients will receive single dose 15mg of tolvaptan via a gastric tube and if determined not bioequivalent and no clinical response to oral administration and safe to administer, then last 15 patients will receive 30mg single dose via a gastric tube.	Over 36 hours from drug administration
Area under the plasma concentration time curve (AUC) of tolvaptan from time zero to 36 hours post-dose	AUC will be computed from 0 to 36 hours using the linear-log trapezoidal method and extrapolated to infinity. Tolvaptan concentrations will be determined using a validated LS/MS/MS assay is sodium heparinized plasma. The tolvaptan assay has a range of 1.00 - 200 mg/mL. Blood samples will be collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 30 and 36 hours after the dose of tolvaptan is administered. The first 15 patients will receive single dose 15mg of tolvaptan via a gastric tube and if determined not bioequivalent and no clinical response to oral administration and safe to administer, then last 15 patients will receive 30mg single dose via a gastric tube.	Over 36 hours from drug administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The clinical response of tolvaptan administered through the nasogastric tube in acute brain injured patients	Clinical response is defined as a change in serum sodium of 4 - 6 mEq/L	Over 36 hours from drug administration
The safety of tolvaptan administered via a nasogastric tube in acute brain injured patients	Safety assessments will include: vital signs, clinical laboratory tests, concomitant medications, and reported or observed adverse events. The rate of sodium correction will also be assessed. Excessive correction in sodium is defined as ≥ 12 mE/L increased in serum sodium within 24 hours of the dose. Excessive drop in blood pressure will be defined as >20% reduction in MAP from baseline.	Over 36 hours from drug administration

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: Medical University of South Carolina; Otsuka America Pharmaceutical; Barnes-Jewish Hospital
• Investigators: Principal Investigator: Kathryn A Morbitzer, PharmD, University of North Carolina, Chapel Hill; Principal Investigator: Denise H. Rhoney, PharmD, University of North Carolina, Chapel Hill

Study record dates

Study Major Dates

• Study Start: November 1, 2014
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): August 1, 2016

Study Registration Dates

• First Submitted: August 11, 2014
• First Submitted That Met QC Criteria: August 11, 2014
• First Posted (Estimate): August 13, 2014

Study Record Updates

• Last Update Posted (Estimate): September 8, 2016
• Last Update Submitted That Met QC Criteria: September 6, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Water-Electrolyte Imbalance; Brain Injuries; Hyponatremia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Antidiuretic Hormone Receptor Antagonists; Tolvaptan
• Other Study ID Numbers: 13-3991; 20141663 (Other Grant/Funding Number: Otsuka America Pharmaceutical, Inc.)