Muscular Atrophy, Spinal
Conditions
Brief summary
This is a multi-center, open-label, non-randomized, parallel-group, 2-part study to evaluate the effect of hepatic impairment on the PK and safety and tolerability of a single oral dose of risdiplam compared to matched healthy participants with normal hepatic function.
Interventions
DRUGRisdiplam
5 milligram (mg) oral dose administered in fasted state
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
All Participants: * BMI between 18.0 and 36.0 kilograms per square metre (kg/m2), inclusive, and body weight \> / = 50 kg * Females must not be pregnant or lactating and must be of non-childbearing potential * Male participants (whether surgically sterilized or not) with female partners of childbearing potential must use methods of contraception from Screening until 4 months after their dose of the study drug as detailed in the protocol * Male participants must not donate sperm from Check-in (Day -1) until 4 months after their dose of the study drug Participants with Normal Hepatic Function Only: * Matched to participants with mild or moderate hepatic function in sex, age, BMI, and smoking status * In good health, as determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital sign measurements, and clinical laboratory evaluations Participants with Hepatic Impairment Only: * Documented chronic stable liver disease * Currently on a stable medication regimen, defined as not starting new drug(s) or changing drug dose(s) within 3 months of administration of study drug * Anemia secondary to hepatic disease will be acceptable, if hemoglobin \>/= 9 gram per decilitre (g/dL). Participants must have a platelet count \</= 35 000 platelets
Exclusion criteria
All Participants * Significant history or clinical manifestation of any metabolic, allergic, dermatological, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder * History of significant hypersensitivity, intolerance, or allergy to any drug compound, constituents or excipients of the study drug, food, or other substance * History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered * Ventricular dysfunction or history of risk factors for Torsades de Pointes * Evidence of hepatorenal syndrome and estimated creatinine clearance range \< 60 millilitre per minute (mL/min) or abnormal sodium and potassium levels * Clinically significant physical examination abnormality * History of diabetes mellitus * Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's Wort * Positive human immunodeficiency virus (HIV) test * Participation in a clinical study involving administration of an investigational drug prior to dosing * Smoke more than 10 cigarettes or use the equivalent tobacco- or nicotine-containing products per day * Receipt of blood products within 2 months prior to study * Donation of blood, plasma, or platelets prior to Screening * Poor peripheral venous access * Have previously completed or withdrawn from this study or any other study investigating risdiplam, and have previously received the investigational product Participants with Normal Hepatic Function Only: * Confirmed supine blood pressure \> 150 millimetre of mercury (mmHg) or \< 90 mmHg * Positive test for hepatitis B or C virus * Clinically significant abnormal laboratory values * Significant history or clinical manifestation of hepatic disorder * History or presence of liver disease or liver injury * Use or intend to use any prescription medications/products within 14 days prior to dosing -. Use or intend to use slow-release medications/products considered to still be active within 14 days prior to dosing * Use or intend to use any non-prescription medications/products within 7 days prior to dosing Participants with Hepatic Impairment Only: * Confirmed supine blood pressure \> 159 mmHg or \< 90 mmHg * Values outside the normal range for liver function tests that are not consistent with their hepatic condition * Use of a new medication, or a change in dose, for the treatment, or worsening of, hepatic encephalopathy * Use of prescription drugs within 14 days of study drug administration * Recent history of, or the treatment of, esophageal bleeding * Presence of a portosystemic shunt * Recent history of paracentesis * Current functioning organ transplant or are waiting for an organ transplant * Evidence of severe ascites * History or current symptoms of hepatic encephalopathy Grade 2 or above
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Risdiplam and Its Metabolite (M1) | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose |
| Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Risdiplam and M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose |
| Part 1: Maximum Observed Plasma Concentration (Cmax) of Risdiplam and M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose |
| Part 2: AUCinf of Risdiplam and M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose |
| Part 2: AUClast of Risdiplam and M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose |
| Part 2: Cmax of Risdiplam and M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: %AUCextrap of Risdiplam and M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose | — |
| Part 2: Tmax of Risdiplam and M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose | — |
| Part 2: t1/2 of Risdiplam and M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose | — |
| Part 1: Time of the Maximum Observed Plasma Concentration (Tmax) of Risdiplam and M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose | — |
| Part 1: Apparent Plasma Terminal Elimination Half-Life (t1/2) of Risdiplam and M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose | — |
| Part 1: Percentage of Area Under the Plasma Concentration-Time Curve Due to Extrapolation (%AUCextrap) of Risdiplam and M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose | — |
| Part 1: Terminal Elimination Rate Constant (λz=Lambda-Z) of Risdiplam and M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose | — |
| Part 1: Apparent Total Clearance (CL/F) of Risdiplam | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose | — |
| Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose | — |
| Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose | — |
| Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose | — |
| Part 2: λz of Risdiplam and M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose | — |
| Part 2: CL/F of Risdiplam and M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose | — |
| Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose | — |
| Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose | — |
| Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1 | Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose | — |
| Part 1 and Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Up to 31 Days | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Mild Hepatic Impairment All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours in Part 1 of the study. | 8 |
| Moderate Hepatic Impairment All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours in Part 2 of the study. | 8 |
| Normal Hepatic Function All participants received a single dose of 5 mg risdiplam orally as a drinking solution on Day 1 after an overnight fast of at least 8 hours. Two normal function participants were matched as controls for mild hepatic impairment participants in Part 1 only; likewise, two normal function participants were matched to moderate hepatic impairment participants in Part 2 only. Six of the normal function participants were matched to mild hepatic impairment participants in Part 1 and also to moderate impairment participants in Part 2. | 10 |
| Total | 26 |
Baseline characteristics
| Characteristic | Mild Hepatic Impairment | Moderate Hepatic Impairment | Normal Hepatic Function | Total |
|---|---|---|---|---|
| Age, Continuous | 61.5 Years STANDARD_DEVIATION 4 | 56.6 Years STANDARD_DEVIATION 6.3 | 57.3 Years STANDARD_DEVIATION 6.8 | 58.4 Years STANDARD_DEVIATION 6.1 |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 3 Participants | 4 Participants | 7 Participants | 14 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 5 Participants | 4 Participants | 3 Participants | 12 Participants |
| Race/Ethnicity, Customized White | 6 Participants | 7 Participants | 10 Participants | 23 Participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 5 Participants | 13 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 5 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 10 |
| other Total, other adverse events | 5 / 8 | 0 / 8 | 0 / 10 |
| serious Total, serious adverse events | 0 / 8 | 1 / 8 | 0 / 10 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Risdiplam and M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Risdiplam and M1 | 773 h*ng/mL | Geometric Coefficient of Variation 20.3 |
| Risdiplam - Normal Hepatic Function | Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Risdiplam and M1 | 961 h*ng/mL | Geometric Coefficient of Variation 35.9 |
| Risdiplam M1 Metabolite - Mild Hepatic Impairment | Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Risdiplam and M1 | 197 h*ng/mL | Geometric Coefficient of Variation 39.1 |
| Risdiplam M1 Metabolite - Normal Hepatic Function | Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Risdiplam and M1 | 245 h*ng/mL | Geometric Coefficient of Variation 47.1 |
Primary
Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Risdiplam and Its Metabolite (M1)
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Risdiplam and Its Metabolite (M1) | 792 h*ng/mL | Geometric Coefficient of Variation 20 |
| Risdiplam - Normal Hepatic Function | Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Risdiplam and Its Metabolite (M1) | 987 h*ng/mL | Geometric Coefficient of Variation 35.2 |
| Risdiplam M1 Metabolite - Mild Hepatic Impairment | Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Risdiplam and Its Metabolite (M1) | 222 h*ng/mL | Geometric Coefficient of Variation 36.6 |
| Risdiplam M1 Metabolite - Normal Hepatic Function | Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Risdiplam and Its Metabolite (M1) | 263 h*ng/mL | Geometric Coefficient of Variation 44.1 |
90% CI: [0.627, 1.03]
90% CI: [0.588, 1.21]
Primary
Part 1: Maximum Observed Plasma Concentration (Cmax) of Risdiplam and M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 1: Maximum Observed Plasma Concentration (Cmax) of Risdiplam and M1 | 21.7 ng/mL | Geometric Coefficient of Variation 23.5 |
| Risdiplam - Normal Hepatic Function | Part 1: Maximum Observed Plasma Concentration (Cmax) of Risdiplam and M1 | 22.8 ng/mL | Geometric Coefficient of Variation 46.9 |
| Risdiplam M1 Metabolite - Mild Hepatic Impairment | Part 1: Maximum Observed Plasma Concentration (Cmax) of Risdiplam and M1 | 3.73 ng/mL | Geometric Coefficient of Variation 30.4 |
| Risdiplam M1 Metabolite - Normal Hepatic Function | Part 1: Maximum Observed Plasma Concentration (Cmax) of Risdiplam and M1 | 3.92 ng/mL | Geometric Coefficient of Variation 36.3 |
90% CI: [0.695, 1.3]
90% CI: [0.715, 1.27]
Primary
Part 2: AUCinf of Risdiplam and M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 2: AUCinf of Risdiplam and M1 | 1040 h*ng/mL | Geometric Coefficient of Variation 29.2 |
| Risdiplam - Normal Hepatic Function | Part 2: AUCinf of Risdiplam and M1 | 971 h*ng/mL | Geometric Coefficient of Variation 30.8 |
| Risdiplam M1 Metabolite - Mild Hepatic Impairment | Part 2: AUCinf of Risdiplam and M1 | 261 h*ng/mL | Geometric Coefficient of Variation 23.4 |
| Risdiplam M1 Metabolite - Normal Hepatic Function | Part 2: AUCinf of Risdiplam and M1 | 275 h*ng/mL | Geometric Coefficient of Variation 33.1 |
90% CI: [0.83, 1.39]
90% CI: [0.74, 1.21]
Primary
Part 2: AUClast of Risdiplam and M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 2: AUClast of Risdiplam and M1 | 1020 h*ng/mL | Geometric Coefficient of Variation 29.7 |
| Risdiplam - Normal Hepatic Function | Part 2: AUClast of Risdiplam and M1 | 947 h*ng/mL | Geometric Coefficient of Variation 31.2 |
| Risdiplam M1 Metabolite - Mild Hepatic Impairment | Part 2: AUClast of Risdiplam and M1 | 243 h*ng/mL | Geometric Coefficient of Variation 24.9 |
| Risdiplam M1 Metabolite - Normal Hepatic Function | Part 2: AUClast of Risdiplam and M1 | 259 h*ng/mL | Geometric Coefficient of Variation 33.9 |
Primary
Part 2: Cmax of Risdiplam and M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 2: Cmax of Risdiplam and M1 | 29.9 ng/mL | Geometric Coefficient of Variation 18.8 |
| Risdiplam - Normal Hepatic Function | Part 2: Cmax of Risdiplam and M1 | 25.0 ng/mL | Geometric Coefficient of Variation 30.2 |
| Risdiplam M1 Metabolite - Mild Hepatic Impairment | Part 2: Cmax of Risdiplam and M1 | 4.10 ng/mL | Geometric Coefficient of Variation 24 |
| Risdiplam M1 Metabolite - Normal Hepatic Function | Part 2: Cmax of Risdiplam and M1 | 4.13 ng/mL | Geometric Coefficient of Variation 22.5 |
90% CI: [0.962, 1.49]
90% CI: [0.81, 1.21]
Secondary
Part 1 and Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time frame: Up to 31 Days
Population: The safety population included all participants who received a dose of risdiplam.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 1 and Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | With at least one AE | 62.5 Percentage of Participants |
| Risdiplam - Mild Hepatic Impairment | Part 1 and Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | With at least one SAE | 0.0 Percentage of Participants |
| Risdiplam - Normal Hepatic Function | Part 1 and Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | With at least one AE | 12.5 Percentage of Participants |
| Risdiplam - Normal Hepatic Function | Part 1 and Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | With at least one SAE | 12.5 Percentage of Participants |
| Risdiplam M1 Metabolite - Mild Hepatic Impairment | Part 1 and Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | With at least one SAE | 0.0 Percentage of Participants |
| Risdiplam M1 Metabolite - Mild Hepatic Impairment | Part 1 and Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | With at least one AE | 0.0 Percentage of Participants |
Secondary
Part 1: Apparent Plasma Terminal Elimination Half-Life (t1/2) of Risdiplam and M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 1: Apparent Plasma Terminal Elimination Half-Life (t1/2) of Risdiplam and M1 | 41.3 h | Geometric Coefficient of Variation 29.1 |
| Risdiplam - Normal Hepatic Function | Part 1: Apparent Plasma Terminal Elimination Half-Life (t1/2) of Risdiplam and M1 | 55.0 h | Geometric Coefficient of Variation 16.2 |
| Risdiplam M1 Metabolite - Mild Hepatic Impairment | Part 1: Apparent Plasma Terminal Elimination Half-Life (t1/2) of Risdiplam and M1 | 32.9 h | Geometric Coefficient of Variation 19.1 |
| Risdiplam M1 Metabolite - Normal Hepatic Function | Part 1: Apparent Plasma Terminal Elimination Half-Life (t1/2) of Risdiplam and M1 | 38.2 h | Geometric Coefficient of Variation 18.7 |
Secondary
Part 1: Apparent Total Clearance (CL/F) of Risdiplam
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 1: Apparent Total Clearance (CL/F) of Risdiplam | 6.31 L/h | Geometric Coefficient of Variation 20 |
| Risdiplam - Normal Hepatic Function | Part 1: Apparent Total Clearance (CL/F) of Risdiplam | 5.07 L/h | Geometric Coefficient of Variation 35.2 |
Secondary
Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1 | 0.258 Ratio | Geometric Coefficient of Variation 22.7 |
| Risdiplam - Normal Hepatic Function | Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1 | 0.255 Ratio | Geometric Coefficient of Variation 12 |
Secondary
Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1 | 0.244 Ratio | Geometric Coefficient of Variation 24.8 |
| Risdiplam - Normal Hepatic Function | Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1 | 0.245 Ratio | Geometric Coefficient of Variation 13.8 |
Secondary
Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1 | 0.165 Ratio | Geometric Coefficient of Variation 29.4 |
| Risdiplam - Normal Hepatic Function | Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1 | 0.164 Ratio | Geometric Coefficient of Variation 15.5 |
Secondary
Part 1: Percentage of Area Under the Plasma Concentration-Time Curve Due to Extrapolation (%AUCextrap) of Risdiplam and M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 1: Percentage of Area Under the Plasma Concentration-Time Curve Due to Extrapolation (%AUCextrap) of Risdiplam and M1 | 2.34 Percentage (%) of AUCextrap | Geometric Coefficient of Variation 29.1 |
| Risdiplam - Normal Hepatic Function | Part 1: Percentage of Area Under the Plasma Concentration-Time Curve Due to Extrapolation (%AUCextrap) of Risdiplam and M1 | 2.53 Percentage (%) of AUCextrap | Geometric Coefficient of Variation 32.8 |
| Risdiplam M1 Metabolite - Mild Hepatic Impairment | Part 1: Percentage of Area Under the Plasma Concentration-Time Curve Due to Extrapolation (%AUCextrap) of Risdiplam and M1 | 7.49 Percentage (%) of AUCextrap | Geometric Coefficient of Variation 54 |
| Risdiplam M1 Metabolite - Normal Hepatic Function | Part 1: Percentage of Area Under the Plasma Concentration-Time Curve Due to Extrapolation (%AUCextrap) of Risdiplam and M1 | 6.28 Percentage (%) of AUCextrap | Geometric Coefficient of Variation 38.7 |
Secondary
Part 1: Terminal Elimination Rate Constant (λz=Lambda-Z) of Risdiplam and M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 1: Terminal Elimination Rate Constant (λz=Lambda-Z) of Risdiplam and M1 | 0.0168 h-1 | Geometric Coefficient of Variation 29.1 |
| Risdiplam - Normal Hepatic Function | Part 1: Terminal Elimination Rate Constant (λz=Lambda-Z) of Risdiplam and M1 | 0.0126 h-1 | Geometric Coefficient of Variation 16.2 |
| Risdiplam M1 Metabolite - Mild Hepatic Impairment | Part 1: Terminal Elimination Rate Constant (λz=Lambda-Z) of Risdiplam and M1 | 0.0211 h-1 | Geometric Coefficient of Variation 19.1 |
| Risdiplam M1 Metabolite - Normal Hepatic Function | Part 1: Terminal Elimination Rate Constant (λz=Lambda-Z) of Risdiplam and M1 | 0.0182 h-1 | Geometric Coefficient of Variation 18.7 |
Secondary
Part 1: Time of the Maximum Observed Plasma Concentration (Tmax) of Risdiplam and M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 1: Time of the Maximum Observed Plasma Concentration (Tmax) of Risdiplam and M1 | 4.00 hours (h) |
| Risdiplam - Normal Hepatic Function | Part 1: Time of the Maximum Observed Plasma Concentration (Tmax) of Risdiplam and M1 | 4.00 hours (h) |
| Risdiplam M1 Metabolite - Mild Hepatic Impairment | Part 1: Time of the Maximum Observed Plasma Concentration (Tmax) of Risdiplam and M1 | 10.00 hours (h) |
| Risdiplam M1 Metabolite - Normal Hepatic Function | Part 1: Time of the Maximum Observed Plasma Concentration (Tmax) of Risdiplam and M1 | 10.00 hours (h) |
Secondary
Part 2: %AUCextrap of Risdiplam and M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 2: %AUCextrap of Risdiplam and M1 | 1.90 Percentage (%) of AUCextrap | Geometric Coefficient of Variation 33.5 |
| Risdiplam - Normal Hepatic Function | Part 2: %AUCextrap of Risdiplam and M1 | 2.41 Percentage (%) of AUCextrap | Geometric Coefficient of Variation 30.5 |
| Risdiplam M1 Metabolite - Mild Hepatic Impairment | Part 2: %AUCextrap of Risdiplam and M1 | 6.58 Percentage (%) of AUCextrap | Geometric Coefficient of Variation 28.8 |
| Risdiplam M1 Metabolite - Normal Hepatic Function | Part 2: %AUCextrap of Risdiplam and M1 | 5.68 Percentage (%) of AUCextrap | Geometric Coefficient of Variation 23.6 |
Secondary
Part 2: CL/F of Risdiplam and M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 2: CL/F of Risdiplam and M1 | 4.79 L/h | Geometric Coefficient of Variation 29.2 |
| Risdiplam - Normal Hepatic Function | Part 2: CL/F of Risdiplam and M1 | 5.15 L/h | Geometric Coefficient of Variation 30.8 |
Secondary
Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1 | 0.239 Ratio | Geometric Coefficient of Variation 16.8 |
| Risdiplam - Normal Hepatic Function | Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1 | 0.271 Ratio | Geometric Coefficient of Variation 10.3 |
Secondary
Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1 | 0.227 Ratio | Geometric Coefficient of Variation 16.8 |
| Risdiplam - Normal Hepatic Function | Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1 | 0.262 Ratio | Geometric Coefficient of Variation 10 |
Secondary
Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1 | 0.131 Ratio | Geometric Coefficient of Variation 16.3 |
| Risdiplam - Normal Hepatic Function | Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1 | 0.158 Ratio | Geometric Coefficient of Variation 15 |
Secondary
Part 2: t1/2 of Risdiplam and M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 2: t1/2 of Risdiplam and M1 | 45.6 h | Geometric Coefficient of Variation 28 |
| Risdiplam - Normal Hepatic Function | Part 2: t1/2 of Risdiplam and M1 | 49.9 h | Geometric Coefficient of Variation 28.1 |
| Risdiplam M1 Metabolite - Mild Hepatic Impairment | Part 2: t1/2 of Risdiplam and M1 | 34.5 h | Geometric Coefficient of Variation 24.3 |
| Risdiplam M1 Metabolite - Normal Hepatic Function | Part 2: t1/2 of Risdiplam and M1 | 35.0 h | Geometric Coefficient of Variation 21.6 |
Secondary
Part 2: Tmax of Risdiplam and M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 2: Tmax of Risdiplam and M1 | 2.00 hours (h) |
| Risdiplam - Normal Hepatic Function | Part 2: Tmax of Risdiplam and M1 | 4.00 hours (h) |
| Risdiplam M1 Metabolite - Mild Hepatic Impairment | Part 2: Tmax of Risdiplam and M1 | 24.00 hours (h) |
| Risdiplam M1 Metabolite - Normal Hepatic Function | Part 2: Tmax of Risdiplam and M1 | 11.00 hours (h) |
Secondary
Part 2: λz of Risdiplam and M1
Time frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose
Population: The PK population included all participants who received a dose of risdiplam and had evaluable PK data. A participant was excluded from the PK descriptive statistics and statistical analysis if the participant had an AE of vomiting that occurred at or before 2 times median time to maximum concentration or if they had any major protocol deviation(s) thought to impact PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Risdiplam - Mild Hepatic Impairment | Part 2: λz of Risdiplam and M1 | 0.0152 h-1 | Geometric Coefficient of Variation 28 |
| Risdiplam - Normal Hepatic Function | Part 2: λz of Risdiplam and M1 | 0.0139 h-1 | Geometric Coefficient of Variation 28.1 |
| Risdiplam M1 Metabolite - Mild Hepatic Impairment | Part 2: λz of Risdiplam and M1 | 0.0201 h-1 | Geometric Coefficient of Variation 24.3 |
| Risdiplam M1 Metabolite - Normal Hepatic Function | Part 2: λz of Risdiplam and M1 | 0.0198 h-1 | Geometric Coefficient of Variation 21.6 |