Pharmacokinetics and Clinical Response of Tolvaptan in Neurocritical Care Patients

Terminated

• Conditions: Brain Injury; Hyponatremia
• Interventions: Drug: Tolvaptan

• Registration Number: NCT02215148
• Lead Sponsor: University of North Carolina, Chapel Hill

Brief Summary

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

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-08-11
• Study First Submitted QC: 2014-08-11
• Study First Posted: 2014-08-13
• Study Start: 2014-11
• Primary Completion: 2016-08
• Study Completion: 2016-08
• Status Verified: 2016-09
• Last Update Submitted: 2016-09-06
• Last Update Posted: 2016-09-08

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 1

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 & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
The elimination rate constant (ke) of tolvaptan over 36 hours post-dose	Over 36 hours from drug administration	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.
Area under the plasma concentration time curve (AUC) of tolvaptan from time zero to 36 hours post-dose	Over 36 hours from drug administration	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.
Maximum observed plasma concentration (Cmax) and time to maximum observed plasma concentration (Tmax) of tolvaptan over 36 hours post-dose	Over 36 hours from drug administration	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.

Secondary Outcome Measures

Name	Time	Method
The safety of tolvaptan administered via a nasogastric tube in acute brain injured patients	Over 36 hours from drug administration	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.
The clinical response of tolvaptan administered through the nasogastric tube in acute brain injured patients	Over 36 hours from drug administration	Clinical response is defined as a change in serum sodium of 4 - 6 mEq/L

Trial Locations

Locations (3)

Barnes-Jewish Hospital; 🇺🇸 St. Louis, Missouri, United States

Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, United States

University of North Carolina Hospitals; 🇺🇸 Chapel Hill, North Carolina, United States