Healthy Adult Participants
Conditions
Keywords
Radiprodil, Carbamazepine, Itraconazole
Brief summary
This is a Phase 1, open-label, 2-part study in healthy adult participants to evaluate the pharmacokinetics and safety of radiprodil when coadministered with either the CYP3A4 inducer carbamazepine or the CYP3A4 inhibitor itraconazole. Up to 36 participants will be enrolled, with approximately 18 participants in Part A and 18 participants in Part B.
Detailed description
Part A will evaluate the effect of carbamazepine on the plasma pharmacokinetic profile of radiprodil. Participants will receive a single 30 mg oral dose of radiprodil under fed conditions, followed by multiple oral doses of carbamazepine, and then coadministration of radiprodil 30 mg with carbamazepine 300 mg. Part B will evaluate the effect of itraconazole on the plasma pharmacokinetic profile of radiprodil. Participants will receive a single 15 mg oral dose of radiprodil under fed conditions, followed by multiple oral doses of itraconazole, and then coadministration of radiprodil 15 mg with itraconazole 200 mg.
Interventions
DRUGRadiprodil
Radiprodil administered orally as a single dose of 30 mg in Part A or 15 mg in Part B under fed conditions.
DRUGCarbamazepine
Carbamazepine administered orally twice daily at doses of 100 mg, 200 mg, and 300 mg in Part A to evaluate the effect of CYP3A4 induction on the pharmacokinetics of radiprodil.
Itraconazole administered orally at 200 mg once daily in Part B to evaluate the effect of CYP3A4 inhibition on the pharmacokinetics of radiprodil.
Sponsors
GRIN Therapeutics, Inc.
Parexel
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male and female adults aged 18 to 55 years inclusive at Screening. * Body mass index between 18 and 32 kg/m² inclusive and weight of at least 50 kg at Screening. * Healthy in the opinion of the Principal Investigator, based on medical history, physical examination, 12-lead ECG, vital signs, and clinical laboratory assessments. * Female participants must be non-lactating and either of non-childbearing potential, postmenopausal, or, if of childbearing potential, must have negative pregnancy tests and agree to required contraception and ova donation restrictions. * Male participants must agree to sperm donation restrictions and required contraception measures. * For Part A only, participants must not be of Asian descent due to increased risk associated with carbamazepine exposure. * Able to provide signed informed consent and comply with study requirements, including dietary restrictions and confinement at the clinical research unit.
Exclusion criteria
* History of contraindication or hypersensitivity to radiprodil, carbamazepine, itraconazole, or formulation components. * For Part A only, HLA genotypes associated with increased risk of carbamazepine-induced severe cutaneous adverse reactions. * Any medical condition that, in the opinion of the Principal Investigator, would pose additional risk or interfere with drug absorption, distribution, metabolism, or excretion. * Pregnancy, breastfeeding, or positive pregnancy test. * Significant neuropsychiatric, cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, urologic, neurological, malignancy, psychiatric disease, brain surgery, or brain injury. * Clinically significant allergic conditions. * History of illicit drug abuse or alcohol abuse within 2 years of Screening. * History of suicide attempt, deliberate self-harm, significant suicidal ideation, or suicidal behaviour on C-SSRS. * Excessive alcohol or caffeine consumption. * Positive drug, alcohol, cotinine, or relevant substance screen at Screening or Day -1. * Recent marijuana, tobacco, nicotine, prescription drug, investigational product, OTC medication, herbal product, vaccine, blood donation, acute illness, relevant surgery, or blood transfusion as defined in the protocol. * Positive serology for HBsAg, HCV antibody, or HIV antibody. * Abnormal blood pressure, pulse rate, clinically significant ECG abnormality, QTcF \>450 msec, or history of prolonged QT syndrome. * Restricted food or drink consumption before dosing, including alcohol, grapefruit/pomelo/star fruit/Seville orange products, poppy seeds, and xanthine-containing products. * Poor venous access. * Women of childbearing potential using oral, injected, or implanted hormonal contraception.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUClast of Radiprodil - Part A | Part A: Day 1 through Day 19 | Area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast) of radiprodil following administration of radiprodil alone on Day 1 and with carbamazepine on Day 16. The effect of carbamazepine will be assessed using the geometric mean ratio and 90% confidence interval. |
| AUCinf of Radiprodil - Part A | Part A: Day 1 through Day 19 | Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUCinf) of radiprodil following administration of radiprodil alone on Day 1 and with carbamazepine on Day 16. The effect of carbamazepine will be assessed using the geometric mean ratio and 90% confidence interval. |
| Cmax of Radiprodil - Part A | Part A: Day 1 through Day 19 | Maximum observed plasma concentration (Cmax) of radiprodil following administration of radiprodil alone on Day 1 and with carbamazepine on Day 16. The effect of carbamazepine will be assessed using the geometric mean ratio and 90% confidence interval. |
| AUClast of Radiprodil - Part B | Part B: Day 1 through Day 12 | Area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast) of radiprodil following administration of radiprodil alone on Day 1 and with itraconazole on Day 9. The effect of itraconazole will be assessed using the geometric mean ratio and 90% confidence interval. |
| AUCinf of Radiprodil - Part B | Part B: Day 1 through Day 12 | Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUCinf) of radiprodil following administration of radiprodil alone on Day 1 and with itraconazole on Day 9. The effect of itraconazole will be assessed using the geometric mean ratio and 90% confidence interval. |
| Cmax of Radiprodil - Part B | Part B: Day 1 through Day 12 | Maximum observed plasma concentration (Cmax) of radiprodil following administration of radiprodil alone on Day 1 and with itraconazole on Day 9. The effect of itraconazole will be assessed using the geometric mean ratio and 90% confidence interval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUClast of Carbamazepine - Part A | Part A: Day 16 (up to 12 hours post-dose) | Area under the plasma concentration-time curve from time zero to the last quantifiable concentration of carbamazepine following administration alone and in combination with radiprodil. |
| AUCtau of Carbamazepine - Part A | Part A: Day 16 (up to 12 hours post-dose) | Area under the plasma concentration-time curve over the 12-hour dosing interval (AUCtau) of carbamazepine following coadministration with radiprodil. |
| Cmax of Carbamazepine - Part A | Part A: Day 16 (up to 12 hours post-dose) | Maximum observed plasma concentration (Cmax) of carbamazepine following coadministration with radiprodil. |
| Tmax of Carbamazepine - Part A | Part A: Day 16 (up to 12 hours post-dose) | Time to reach maximum observed plasma concentration of carbamazepine following administration alone and in combination with radiprodil. |
| AUClast of Itraconazole - Part B | Part B: Day 9 through Day 10 (up to 24 hours post-dose) | Area under the plasma concentration-time curve from time zero to the last quantifiable concentration of itraconazole following administration alone and in combination with radiprodil. |
| AUCtau of Itraconazole - Part B | Part B: Day 9 through Day 10 (up to 24 hours post-dose) | Area under the plasma concentration-time curve over the dosing interval of itraconazole following administration alone and in combination with radiprodil. |
| Cmax of Itraconazole - Part B | Part B: Day 9 through Day 10 (up to 24 hours post-dose) | Maximum observed plasma concentration of itraconazole following administration alone and in combination with radiprodil. |
| Tmax of Itraconazole - Part B | Part B: Day 9 through Day 10 (up to 24 hours post-dose) | Time to reach maximum observed plasma concentration of itraconazole following administration alone and in combination with radiprodil. |
| Tmax of Radiprodil - Part A | Part A: Day 1 through Day 19 | Time to reach maximum observed plasma concentration of radiprodil. Assessed following administration of radiprodil alone and in combination with carbamazepine. |
| Terminal Elimination Half-Life (t½) of Radiprodil - Part A | Part A: Day 1 through Day 19 | Terminal elimination half-life of radiprodil, defined as the time required for plasma concentration to decrease by half during the terminal elimination phase. Assessed following administration of radiprodil alone and in combination with carbamazepine. |
| Apparent Total Body Clearance (CL/F) of Radiprodil - Part A | Part A: Day 1 through Day 19 | Apparent total body clearance of radiprodil following oral administration. Assessed following administration of radiprodil alone and in combination with carbamazepine. |
| Apparent Volume of Distribution (Vz/F) of Radiprodil - Part A | Part A: Day 1 through Day 19 | Apparent volume of distribution of radiprodil during the terminal elimination phase following oral administration. Assessed following administration of radiprodil alone and in combination with carbamazepine. |
| Tmax of Radiprodil - Part B | Part B: Day 1 through Day 12 | Time to reach maximum observed plasma concentration of radiprodil. Assessed following administration of radiprodil alone and in combination with itraconazole. |
| Terminal Elimination Half-Life (t½) of Radiprodil - Part B | Part B: Day 1 through Day 12 | Terminal elimination half-life of radiprodil, defined as the time required for plasma concentration to decrease by half during the terminal elimination phase. Assessed following administration of radiprodil alone and in combination with itraconazole. |
| Apparent Total Body Clearance (CL/F) of Radiprodil - Part B | Part B: Day 1 through Day 12 | Apparent total body clearance of radiprodil following oral administration. Assessed following administration of radiprodil alone and in combination with itraconazole. |
| Apparent Volume of Distribution (Vz/F) of Radiprodil - Part B | Part B: Day 1 through Day 12 | Apparent volume of distribution of radiprodil during the terminal elimination phase following oral administration. Assessed following administration of radiprodil alone and in combination with itraconazole. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From first dose of study drug through follow-up (up to approximately 90 days in Part A and 69 days in Part B) | Number and percentage of participants with at least one treatment-emergent adverse event (TEAE), summarised by treatment period and overall for each study part. TEAEs are adverse events occurring or worsening after the first dose of study drug. |
| Number of Participants With Serious Adverse Events (SAEs) | From signing of informed consent through follow-up (up to approximately 90 days in Part A and 69 days in Part B) | Number of participants experiencing at least one serious adverse event, summarised separately for each study part. |
| Change From Baseline in Systolic Blood Pressure | From baseline through follow-up | Change from baseline in systolic blood pressure, measured in mmHg, summarised by scheduled assessment time point and treatment period within each study part. |
| Change From Baseline in Diastolic Blood Pressure | From baseline through follow-up | Change from baseline in diastolic blood pressure, measured in mmHg, summarised by scheduled assessment time point and treatment period within each study part. |
| Change From Baseline in Pulse Rate | From baseline through follow-up | Change from baseline in pulse rate, measured in beats per minute, summarised by scheduled assessment time point and treatment period within each study part. |
| Change From Baseline in Body Temperature | From baseline through follow-up | Change from baseline in body temperature, measured in degrees Celsius, summarised by scheduled assessment time point and treatment period within each study part. |
| Change From Baseline in Respiratory Rate | From baseline through follow-up | Change from baseline in respiratory rate, measured in breaths per minute, summarised by scheduled assessment time point and treatment period within each study part. |
| Number of Participants With QTcF Interval Above 450 Milliseconds | From baseline through follow-up | Number of participants with a QT interval corrected using Fridericia's formula (QTcF) greater than 450 milliseconds during the study. |
| Number of Participants With QTcF Interval Above 480 Milliseconds | From baseline through follow-up | Number of participants with a QTcF interval greater than 480 milliseconds during the study. |
| Number of Participants With QTcF Interval Above 500 Milliseconds | From baseline through follow-up | Number of participants with a QTcF interval greater than 500 milliseconds during the study. |
| Number of Participants With QTcF Increase From Baseline of at Least 30 Milliseconds | From baseline through follow-up | Number of participants with an increase in QTcF from baseline of at least 30 milliseconds during the study. |
| Number of Participants With QTcF Increase From Baseline of at Least 60 Milliseconds | From baseline through follow-up | Number of participants with an increase in QTcF from baseline of at least 60 milliseconds during the study. |
Countries
United States
Outcome results
None listed