Hepatic Impairment
Conditions
Keywords
Hepatic impairment, Radiprodil
Brief summary
This Phase 1, open-label study will evaluate the pharmacokinetics (PK), safety, and tolerability of a single oral dose of radiprodil in adults with varying degrees of hepatic impairment compared with healthy participants. Radiprodil is being developed as a potential treatment for GRIN-related neurodevelopmental disorders, tuberous sclerosis complex, and focal cortical dysplasia. Approximately 40 adults aged 18 to 75 years will be enrolled into five cohorts based on liver function (mild, moderate, or severe hepatic impairment) or healthy status. Participants will receive a single 15 mg oral dose of radiprodil and remain in the clinical research unit for intensive PK and safety monitoring through Day 6. The primary objective is to characterize the PK profile of radiprodil in participants with hepatic impairment compared with healthy participants. Safety and tolerability will also be assessed. Results from this study will help determine whether dose adjustments are needed in individuals with impaired liver function.
Detailed description
This is a Phase 1, open-label, two-arm study designed to assess the pharmacokinetics (PK), safety, and tolerability of a single oral dose of radiprodil in adults with varying degrees of hepatic impairment compared with matched healthy participants. Up to 40 participants aged 18 to 75 years will be enrolled across five cohorts. Participants will include individuals with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment, as well as healthy participants matched for age, sex, and body mass index where feasible. The study consists of a Screening Period (Days -28 to -2), check-in on Day -1, and a Treatment Period. Participants will be confined to the clinical research unit from Day -1 through completion of study assessments on Day 6. On Day 1, all participants will receive a single oral dose of radiprodil 15 mg administered as an oral suspension. Serial blood samples will be collected to determine plasma concentrations of radiprodil and its major metabolites. Key PK parameters include area under the concentration-time curve (AUC), maximum observed concentration (Cmax), time to maximum concentration (Tmax), terminal half-life (t½), apparent clearance (CL/F), and apparent volume of distribution (Vz/F). Safety and tolerability will be evaluated throughout the study by monitoring adverse events, vital signs, electrocardiograms, clinical laboratory tests, physical examinations, and Columbia Suicide Severity Rating Scale assessments. Hepatic impairment can alter the metabolism and exposure of many drugs. Because radiprodil is primarily eliminated via hepatic metabolism, this study is intended to characterize the effect of liver impairment on radiprodil exposure and to inform potential dosing recommendations for future clinical use.
Interventions
DRUGRadiprodil
Radiprodil will be administered as a single oral dose of 15 mg (2.0 mL of 7.5 mg/mL oral suspension) on Day 1 under fed conditions. Participants will fast overnight for at least 10 hours prior to dosing and consume a standard breakfast approximately 30 minutes before administration. Study drug will be administered with approximately 240 mL of water. All participants across cohorts will receive the same single-dose regimen.
Sponsors
GRIN Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Intervention model description
Participants will be assigned to parallel cohorts based on hepatic function (mild, moderate, or severe hepatic impairment) or healthy status. All participants will receive a single oral dose of radiprodil 15 mg. Healthy participants will be enrolled to match hepatically impaired cohorts by age, sex, and body mass index where feasible. Cohorts will be initiated sequentially following Safety Review Committee review of available safety and pharmacokinetic data, but participants will not cross over between cohorts.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Male or female participants aged 18 to 75 years, inclusive, at Screening. * Body mass index (BMI) within the range specified in the protocol. * Participants with hepatic impairment must have stable mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment, as applicable to cohort assignment. * Healthy participants must be medically healthy with no clinically significant abnormalities as determined by the investigator. * Participants must be willing and able to comply with all study procedures and confinement requirements. * Participants of childbearing potential must agree to use highly effective contraception methods as defined in the protocol. * Participants must provide written informed consent prior to any study procedures
Exclusion criteria
* History or presence of clinically significant medical conditions that could interfere with study participation or interpretation of results. * Positive test for drugs of abuse, alcohol, or cotinine (where applicable) at Screening or check-in. * Positive serology for HIV, hepatitis B surface antigen, or hepatitis C virus. * Clinically significant abnormal laboratory values, vital signs, or ECG findings at Screening or Day -1, as judged by the investigator. * Use of prohibited concomitant medications or substances that may interfere with radiprodil metabolism. * Pregnant or breastfeeding women. * Participation in another clinical study or receipt of an investigational product within the protocol-specified timeframe prior to dosing. * Any condition that, in the opinion of the investigator or sponsor, would make participation not in the best interest of the participant or could confound study results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time Before First Quantifiable Plasma Concentration (Tlag) of Radiprodil | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma Tlag of radiprodil following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Apparent Total Body Clearance (CL/F) of Radiprodil | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Apparent total body clearance of radiprodil following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Apparent Volume of Distribution Based on the Terminal Phase (Vz/F) of Radiprodil | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Apparent volume of distribution of radiprodil following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Terminal Elimination Half-Life (t½) of Radiprodil | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma terminal elimination half-life of radiprodil following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Area Under the Plasma Concentration-Time Curve from Time 0 to Time of Last Quantifiable Concentration (AUClast) of Radiprodil | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma AUClast of radiprodil following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Area Under the Plasma Concentration-Time Curve from Time 0 Extrapolated to Infinity (AUCinf) of Radiprodil | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma AUCinf of radiprodil following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Maximum Observed Plasma Concentration (Cmax) of Radiprodil | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma Cmax of radiprodil following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Time to Maximum Observed Plasma Concentration (Tmax) of Radiprodil | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma Tmax of radiprodil following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) Score | Baseline (Day -1) through Day 6 (120 hours post-dose) | Change from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) score following a single oral dose of radiprodil. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Day 1 through Day 6 (120 hours post-dose) | Incidence of treatment-emergent adverse events following a single oral dose of radiprodil, summarized by system organ class and preferred term. |
| Number of Participants With Serious Adverse Events (SAEs) | Day 1 through Day 6 (120 hours post-dose) | Incidence of serious adverse events following a single oral dose of radiprodil. |
| Area Under the Plasma Concentration-Time Curve from Time 0 to Time of Last Quantifiable Concentration (AUClast) of FBPO | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma AUClast of the radiprodil major metabolite FBPO following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants |
| Area Under the Plasma Concentration-Time Curve from Time 0 Extrapolated to Infinity (AUCinf) of FBPO | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma AUCinf of FBPO following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Maximum Observed Plasma Concentration (Cmax) of FBPO | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma Cmax of FBPO following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Time to Maximum Observed Plasma Concentration (Tmax) of FBPO | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma Tmax of FBPO following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Time Before First Quantifiable Plasma Concentration (Tlag) of FBPO | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma Tlag of FBPO following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Terminal Elimination Half-Life (t½) of FBPO | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma terminal half-life of FBPO following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Area Under the Plasma Concentration-Time Curve from Time 0 to Time of Last Quantifiable Concentration (AUClast) of ORR-S | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma AUClast of the radiprodil major metabolite ORR-S following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Area Under the Plasma Concentration-Time Curve from Time 0 Extrapolated to Infinity (AUCinf) of ORR-S | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma AUCinf of ORR-S following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Maximum Observed Plasma Concentration (Cmax) of ORR-S | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma Cmax of ORR-S following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Time to Maximum Observed Plasma Concentration (Tmax) of ORR-S | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma Tmax of ORR-S following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Time Before First Quantifiable Plasma Concentration (Tlag) of ORR-S | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma Tlag of ORR-S following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Number of Participants With Adverse Events Leading to Discontinuation | Day 1 through Day 6 (120 hours post-dose) | Incidence of participants who discontinue the study due to an adverse event following a single oral dose of radiprodil. |
| Terminal Elimination Half-Life (t½) of ORR-S | Day 1 (pre-dose) through Day 6 (120 hours post-dose) | Plasma terminal half-life of ORR-S following a single oral dose in participants with varying degrees of hepatic impairment and healthy participants. |
| Change From Baseline in Systolic Blood Pressure (mmHg) | Baseline (Day -1) through Day 6 (120 hours post-dose) | Change from baseline in systolic blood pressure following a single oral dose of radiprodil. |
| Change From Baseline in Diastolic Blood Pressure (mmHg) | Baseline (Day -1) through Day 6 (120 hours post-dose) | Change from baseline in diastolic blood pressure following a single oral dose of radiprodil. |
| Change From Baseline in Heart Rate (beats per minute) | Baseline (Day -1) through Day 6 (120 hours post-dose) | Change from baseline in heart rate following a single oral dose of radiprodil. |
| Change From Baseline in Respiratory Rate (breaths per minute) | Baseline (Day -1) through Day 6 (120 hours post-dose) | Change from baseline in respiratory rate following a single oral dose of radiprodil. |
| Change From Baseline in Body Temperature (°C) | Baseline (Day -1) through Day 6 (120 hours post-dose) | Change from baseline in body temperature following a single oral dose of radiprodil. |
| Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) (milliseconds) | Baseline (Day -1) through Day 6 (120 hours post-dose) | Change from baseline in QT interval corrected using Fridericia's formula (QTcF) following a single oral dose of radiprodil. |
| Number of Participants With Clinically Significant Laboratory Abnormalities | Baseline (Day -1) through Day 6 (120 hours post-dose) | Incidence of participants with laboratory values meeting predefined criteria for clinical significance across hematology, serum chemistry, coagulation, and urinalysis following a single oral dose of radiprodil. |
Countries
United States
Contacts
CONTACTLaura Bardell
CONTACTAneeta Saxena
Outcome results
None listed