Pharmacokinetics and Clinical Response of Tolvaptan in Neurocritical Care Patients

NCT02215148 | Terminated DMC

• 2 other identifiers: 13-399120141663
• Study Type: observational
• Target: 1
• Locations: 1 country
• Sites: 3

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

Conditions

Brain Injury; Hyponatremia

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (2)

• The clinical response of tolvaptan administered through the nasogastric tube in acute brain injured patients

  Over 36 hours from drug administration

• The safety of tolvaptan administered via a nasogastric tube in acute brain injured patients

  Over 36 hours from drug administration

Study Arms (1)

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

Interventions

Tolvaptan DRUG

Brain injured patients with hyponatremia

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

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

You may qualify if:

• 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
• Informed consent obtained from patient or authorized legal representative
• Age ≥ 18 years

You may not qualify if:

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

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• Otsuka America Pharmaceutical: collaborator
• Medical University of South Carolina: collaborator
• Barnes-Jewish Hospital: collaborator

Study Sites (3)

Barnes-Jewish Hospital

St Louis, Missouri, 63110, United States

Location

University of North Carolina Hospitals

Chapel Hill, North Carolina, 27599, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Biospecimen

Retention: SAMPLES WITHOUT DNA

Blood samples for pharmacokinetic sampling will be collected in serum separator tubes at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 30 and 36 hours after the dose of study drug is administered. Serum sodium will be collected at baseline and 2, 4, 6, 8, 12, 24, and 36 hours after study drug administration. Approximately 180 mL of blood will be collected over 36 hours. Urinary output and urine specific gravity will be collected 0-2, 2-4, 3-6, 6-8, 8-12, and 12-24 hours after tolvaptan administration.

MeSH Terms

Conditions

Brain Injuries; Hyponatremia

Interventions

Tolvaptan

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries; Water-Electrolyte Imbalance; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Kathryn A Morbitzer, PharmD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

• Denise H. Rhoney, PharmD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 11, 2014
• First Posted: August 13, 2014
• Study Start: November 1, 2014
• Primary Completion: August 1, 2016
• Study Completion: August 1, 2016
• Last Updated: September 8, 2016

Record last verified: 2016-09

Locations

US (3)