The Effect of Hepatic Impairment on the Pharmacokinetics of Balovaptan

NCT03912350 | Withdrawn Phase 1 FDA Drug

• 1 other identifier: WP41045
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a multi-center, non-randomized, open-label, parallel group, multiple-dose study to assess the pharmacokinetic, safety, and tolerability of balovaptan in male and female subjects with moderate hepatic impairment compared to healthy subjects with normal hepatic function matched by age (±10 years), sex, and body mass index (BMI; ±20%).

Conditions

Autism Spectrum Disorder

Outcome Measures

Primary Outcomes (34)

• Plasma concentration of balovaptan

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16 hours post-dose on Day 1; pre-dose on Day 2 to Day 13; pre-dose and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Plasma concentration of M2 metabolite, as applicable

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16 hours post-dose on Day 1; pre-dose on Day 2 to Day 13; pre-dose and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Plasma concentration of M3 metabolite

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16 hours post-dose on Day 1; pre-dose on Day 2 to Day 13; pre-dose and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• AUC during the dosing interval on Day 1 of balovaptan

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1

• AUC during the dosing interval on Day 1 of M2 metabolite

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1

• AUC during the dosing interval on Day 1 of M3 metabolite

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1

• AUC during the dosing interval at steady state on Day 14 of balovaptan

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• AUC during the dosing interval at steady state on Day 14 of M2 metabolite

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• AUC during the dosing interval at steady state on Day 14 of M3 metabolite

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Maximum observed plasma concentration (Cmax) of balovaptan

  1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Maximum observed plasma concentration (Cmax) of M2 metabolite

  1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Maximum observed plasma concentration (Cmax) of M3 metabolite

  1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Time of maximum observed plasma concentration (Tmax) of balovaptan

  1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Time of maximum observed plasma concentration (Tmax) of M2 metabolite

  1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Time of maximum observed plasma concentration (Tmax) of M3 metabolite

  1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Metabolite:Parent ratio of area under the plasma (MRauc) of M2 metabolite

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Metabolite:Parent ratio of area under the plasma (MRauc) of M3 metabolite

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Metabolite:Parent ratio of maximum observed plasma (MRcmax) of M2 metabolite

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Metabolite:Parent ratio of maximum observed plasma (MRcmax) of M3 metabolite

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Apparent volume of distribution (V/F) of balovaptan

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Apparent volume of distribution (V/F) of M2 metabolite

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Apparent volume of distribution (V/F) of M3 metabolite

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Terminal phase rate constant (λZ) of balovaptan, when possible

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Terminal phase rate constant (λZ) of M2 metabolite, when possible

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Terminal phase rate constant (λZ) of M3 metabolite, when possible

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Apparent terminal elimination half-life (t½) of balovaptan, when possible

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Apparent terminal elimination half-life (t½) of M2 metabolite, when possible

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Apparent terminal elimination half-life (t½) of M3 metabolite, when possible

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Apparent plasma clearance after oral administration (CLss/F) of balovaptan, when possible

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Apparent plasma clearance after oral administration (CLss/F) of M2 metabolite, when possible

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Apparent plasma clearance after oral administration (CLss/F) of M3 metabolite, when possible

  Pre-dose, and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Apparent volume of distribution based on the terminal phase after oral administration (Vz/F) of balovaptan, when possible

  1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Apparent volume of distribution based on the terminal phase after oral administration (Vz/F) of M2 metabolite, when possible

  1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

• Apparent volume of distribution based on the terminal phase after oral administration (Vz/F) of M3 metabolite, when possible

  1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 1; pre-dose and 1, 2, 3, 4, 5, 6, 9, 12, 16, and 24 hours post-dose on Day 14

Secondary Outcomes (1)

• Percentage of participants with adverse events

  Up to approximately 18 weeks from screening (screening is up to 28 days prior to admission to the clinical research unit).

Study Arms (2)

Test group

EXPERIMENTAL

Participants with moderate hepatic impairment.

Drug: Balovaptan

Reference group

ACTIVE COMPARATOR

Healthy pariticipants with normal hepatic function.

Drug: Balovaptan

Interventions

Balovaptan DRUG

Participants will receive 1 tablet of balovaptan once daily (QD) on Days 1 through 14.

Reference group; Test group

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• BMI between 18 and 40 kg/m2, inclusive.
• Women of childbearing potential must either: agree to use one highly effective contraceptive method combined with a barrier method from Screening until 90 days after the last dose of study drug or practice true abstinence because of the subject's lifestyle choice; be in an exclusively same-sex relationship.
• For men: agreement to use contraceptive measures
• Females of child-bearing potential must refrain from donating ova from Day -1 until 90 days after the safety Follow-up visit. Males must refrain from donating sperm from Day -1 until 90 days after the safety Follow-up visit.
• Stable, documented moderate liver disease diagnosed \>6 months and stable for at least 3 months prior to Screening.
• Participants with moderate hepatic impairment may have medical findings consistent with their hepatic dysfunction. Participants with abnormal findings considered in line with underlying hepatic disease by the Investigator will be eligible.
• Healthy status is defined by no clinically significant findings from medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, hematology, chemistry, and urinalysis at Screening and/or Day -1 as assessed by the Investigator (or designee). Gilbert's syndrome is acceptable.

You may not qualify if:

• History of significant hypersensitivity, intolerance, or allergy to any drug compound, constituents or excipients of the study drug, food, or other substance, unless approved by the Investigator (or designee).
• History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs.
• Evidence of hepatorenal syndrome and estimated creatinine clearance range \<60 mL/min or abnormal and clinically significant sodium and potassium levels, as determined by the Investigator (or designee).
• Female subjects of childbearing potential with a positive serum pregnancy test at Screening and/or at admission (Day -1), or who are lactating.
• History of drug/chemical abuse within 2 years prior to Screening; current active substance abuse will not be permitted.
• Known personal or family history of congenital long QT syndrome or sudden unexplained death.
• History within 3 months prior to Screening, or current symptoms of, hepatic encephalopathy Grade 2 and above.
• Evidence of severe ascites.
• Recent history of, or the treatment of, esophageal bleeding within 3 months of first dose, unless banded.
• Participants who have had a porto-systemic shunt.
• Participants who have a history of paracentesis within 3 months prior to Day -1.
• Participants who have a history of unstable diabetes mellitus as evidenced by hemoglobin A1c ≥ 9% at Screening.
• History of alcoholism within 3 months prior to Screening.
• Use of any prescription drugs within 30 days (or within 5 times the elimination half-life, if known, of the medication, whichever is longer) of first dose, with the exception of therapies for hepatic-associated disorders that have been stable for at least 60 days prior to first dose.
• Biliary liver cirrhosis or other causes of hepatic impairment not related to parenchymal disorder and/or disease of the liver.

Sponsors & Collaborators

• Hoffmann-La Roche: lead

MeSH Terms

Conditions

Autism Spectrum Disorder

Interventions

balovaptan

Condition Hierarchy (Ancestors)

Child Development Disorders, Pervasive; Neurodevelopmental Disorders; Mental Disorders

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 10, 2019
• First Posted: April 11, 2019
• Study Start: June 26, 2022
• Primary Completion: September 24, 2022
• Study Completion: October 13, 2022
• Last Updated: February 8, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share