Hepatic Impairment
Conditions
Keywords
BAF312, Pharmacokinetics, Hepatic impairment
Brief summary
This study will investigate the pharmacokinetics of BAF312 in patients with mild, moderate and severe hepatic impairment compared to healthy control subjects.
Interventions
DRUGBAF312
Treatment with a single oral dose of 0.25 mg BAF312
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
All subjects: * Male and female Caucasian subjects 18 to 70 years of age * At least 50 kg and body mass index (BMI) within 18-35 kg/m2. * CYP2C9 wild-type (CYP2C9\*1 homozygous carriers) Hepatic impairment: \- Subjects must have either mild, moderate or severe hepatic impairment
Exclusion criteria
All subjects * Hepatic impairment due to non-liver disease. * Use of other investigational drugs within certain timelines * Donation or loss of 400 mL or more of blood or plasma within eight (8) weeks prior to initial dosing * History of cardiac rhythm abnormalities or cardiac rhythm abnormalities identified in the 24-h Holter ECG recording including episodes of bradycardia (HR \< 50 bpm) during waking hours and/or arrhythmic episodes; subjects with history or presence of ventricular rhythm disturbances (ventricular extra-systoles \>100/24h, or higher grade), or supraventricular arrhythmias (other than occasional supraventricular ectopic beats with a maximum of 5 subsequent ectopic beats per event) or subjects with conduction disturbances (higher than AV-block grade 1) or bradycardia or tachycardia. * History of cardiac catheter ablation. * Women of child-bearing potential * History of malignancy of any organ system * Recent and/or recurrent history of acute or chronic bronchospastic disease (including asthma and chronic obstructive pulmonary disease) * History or presence of symptomatic postural hypotension or syncope. * Total WBC or lymphocyte counts which falls outside the 1.5-fold local laboratory normal range or platelet count \< 30,000/μL at screening or baseline. * Clinically significant infection or recent vaccination with live-attenuated vaccines. * History or presence of hepatitis B or C and/or positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result at screening. * History or presence of coronary heart disease (stable or unstable), myocardial infarction, myocarditis, cardiomyopathy, heart failure NYHA II - IV. Hepatic impairment: * History or presence of any non-controlled and clinically significant disease that could affect the study outcome or that would place the patient at undue risk. * Any surgical or medical condition other than hepatic impairment which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the safety of the study subject in case of participation in the study. * Treatment with certain drugs Healthy subjects: * History or presence of any clinically significant disease of any major system organ class including (but not limited to) cardiovascular, metabolic, renal, neurological or psychiatric diseases. * Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, drugs, or which may jeopardize the subject in case of participation in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) | pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose. | The pharmacokinetics of BAF312 were studied in plasma up to 504 hours post-dose at the following time points: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose. |
| Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) | pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose. | The pharmacokinetics of BAF312 were studied in plasma up to 504 hours post-dose at the following time points: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose. |
| Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) | pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose | The pharmacokinetics of BAF312 were studied in plasma up to 504 hours post-dose at the following time points: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (Frequency of Adverse Events, Serious Adverse Events, and Notable Laboratory Abnormalities) of of BAF312 After a Single Dose of BAF312 | Day -1 to 22 | Physical examination, vital signs, body temperature, standard safety laboratory evaluations (hematology, clinical chemistry, coagulation, Hepatitis B and C and HIV serology, α-fetoprotein \[in hepatically impaired subjects only\], pregnancy test, alcohol and drug screen), standard 12-lead electrocardiogram , cardiac monitoring, 24-h Holter ECG, suicidality assessment (C-SSRS), (serious) adverse event monitoring. |
Countries
Hungary, Russia
Participant flow
Recruitment details
Up to forty-eight subjects were planned to be enrolled in four groups. A total of 40 subjects were enrolled and completed the study. All subjects were included in the safety and PK analysis. However, only 38 subjects were included for primary PK analysis based on matched pair analysis
Pre-assignment details
To potentially reduce the number of healthy subjects exposed to BAF312, study allowed for multiple matching of subjects with hepatic impairment to healthy subjects. During the study, 2 healthy subjects were not matched to any of the subjects with hepatic impairment due to a retrospective identification of a better matching partner
Participants by arm
| Arm | Count |
|---|---|
| Mild Hepatically Impaired Treatment with a single oral dose of 0.25 mg BAF312 | 8 |
| Moderate Hepatically Impaired Treatment with a single oral dose of 0.25 mg BAF312 | 8 |
| Severe Hepatically Impaired Treatment with a single oral dose of 0.25 mg BAF312 | 8 |
| Matched Healthy Subjects Treatment with a single oral dose of 0.25 mg BAF312 | 16 |
| Total | 40 |
Baseline characteristics
| Characteristic | Mild Hepatically Impaired | Moderate Hepatically Impaired | Severe Hepatically Impaired | Matched Healthy Subjects | Total |
|---|---|---|---|---|---|
| Age, Continuous | 53.9 Years STANDARD_DEVIATION 6.2 | 47.8 Years STANDARD_DEVIATION 6.3 | 51.8 Years STANDARD_DEVIATION 3.41 | 50.1 Years STANDARD_DEVIATION 5.5 | 50.7 Years STANDARD_DEVIATION 5.65 |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants | 6 Participants | 14 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 4 Participants | 10 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 8 | 1 / 8 | 1 / 16 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 16 | 0 / 8 |
Outcome results
Primary
Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf)
The pharmacokinetics of BAF312 were studied in plasma up to 504 hours post-dose at the following time points: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose.
Time frame: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose.
Population: The PK analysis set consists of all completed subjects with quantifiable pharmacokinetic (PK) measurements. To reduce the number of healthy subjects exposed to BAF312, study allowed matching of subjects with hepatic impairment to healthy subjects. A healthy subject served as matching partner for up to 3 subjects with hepatic impairment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatically Impaired | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) | 68.3 h*ng/mL | Standard Deviation 24.5 |
| Moderate Hepatically Impaired | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) | 53.9 h*ng/mL | Standard Deviation 7.57 |
| Severe Hepatically Impaired | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) | 73.7 h*ng/mL | Standard Deviation 25.4 |
| Matched Healthy Subjects - Mild | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) | 64.2 h*ng/mL | Standard Deviation 20.8 |
| Matched Healthy Subjects - Moderate | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) | 63.2 h*ng/mL | Standard Deviation 18.6 |
| Matched Healthy Subjects - Severe | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) | 64.9 h*ng/mL | Standard Deviation 23.6 |
Primary
Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast)
The pharmacokinetics of BAF312 were studied in plasma up to 504 hours post-dose at the following time points: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose.
Time frame: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose.
Population: The PK analysis set consists of all completed subjects with quantifiable pharmacokinetic (PK) measurements. To reduce the number of healthy subjects exposed to BAF312, study allowed matching of subjects with hepatic impairment to healthy subjects. A healthy subject served as matching partner for up to 3 subjects with hepatic impairment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatically Impaired | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) | 66.8 h*ng/mL | Standard Deviation 24.4 |
| Moderate Hepatically Impaired | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) | 52.3 h*ng/mL | Standard Deviation 7.51 |
| Severe Hepatically Impaired | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) | 71.6 h*ng/mL | Standard Deviation 24.5 |
| Matched Healthy Subjects - Mild | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) | 62.5 h*ng/mL | Standard Deviation 20.9 |
| Matched Healthy Subjects - Moderate | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) | 61.7 h*ng/mL | Standard Deviation 18.7 |
| Matched Healthy Subjects - Severe | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) | 63.4 h*ng/mL | Standard Deviation 23.6 |
Primary
Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax)
The pharmacokinetics of BAF312 were studied in plasma up to 504 hours post-dose at the following time points: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose
Time frame: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 144, 216, 312, 408 and 504 hours post dose
Population: The PK analysis set consists of all completed subjects with quantifiable pharmacokinetic (PK) measurements. To reduce the number of healthy subjects exposed to BAF312, study allowed matching of subjects with hepatic impairment to healthy subjects. A healthy subject served as matching partner for up to 3 subjects with hepatic impairment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mild Hepatically Impaired | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) | 2.03 (ng/mL) | Standard Deviation 0.532 |
| Moderate Hepatically Impaired | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) | 1.54 (ng/mL) | Standard Deviation 0.191 |
| Severe Hepatically Impaired | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) | 1.58 (ng/mL) | Standard Deviation 0.304 |
| Matched Healthy Subjects - Mild | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) | 1.74 (ng/mL) | Standard Deviation 0.439 |
| Matched Healthy Subjects - Moderate | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) | 1.80 (ng/mL) | Standard Deviation 0.417 |
| Matched Healthy Subjects - Severe | Pharmacokinetic Parameters of BAF312 and Selected Metabolites: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) | 1.94 (ng/mL) | Standard Deviation 0.603 |
Secondary
Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (Frequency of Adverse Events, Serious Adverse Events, and Notable Laboratory Abnormalities) of of BAF312 After a Single Dose of BAF312
Physical examination, vital signs, body temperature, standard safety laboratory evaluations (hematology, clinical chemistry, coagulation, Hepatitis B and C and HIV serology, α-fetoprotein \[in hepatically impaired subjects only\], pregnancy test, alcohol and drug screen), standard 12-lead electrocardiogram , cardiac monitoring, 24-h Holter ECG, suicidality assessment (C-SSRS), (serious) adverse event monitoring.
Time frame: Day -1 to 22
Population: The safety analysis set consists of all subjects that received study drug and with no protocol deviations with relevant impact on safety.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mild Hepatically Impaired | Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (Frequency of Adverse Events, Serious Adverse Events, and Notable Laboratory Abnormalities) of of BAF312 After a Single Dose of BAF312 | Serious Adverse Events | 0 Participants |
| Mild Hepatically Impaired | Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (Frequency of Adverse Events, Serious Adverse Events, and Notable Laboratory Abnormalities) of of BAF312 After a Single Dose of BAF312 | At least one AE | 0 Participants |
| Mild Hepatically Impaired | Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (Frequency of Adverse Events, Serious Adverse Events, and Notable Laboratory Abnormalities) of of BAF312 After a Single Dose of BAF312 | Death | 0 Participants |
| Moderate Hepatically Impaired | Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (Frequency of Adverse Events, Serious Adverse Events, and Notable Laboratory Abnormalities) of of BAF312 After a Single Dose of BAF312 | At least one AE | 1 Participants |
| Moderate Hepatically Impaired | Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (Frequency of Adverse Events, Serious Adverse Events, and Notable Laboratory Abnormalities) of of BAF312 After a Single Dose of BAF312 | Serious Adverse Events | 0 Participants |
| Moderate Hepatically Impaired | Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (Frequency of Adverse Events, Serious Adverse Events, and Notable Laboratory Abnormalities) of of BAF312 After a Single Dose of BAF312 | Death | 0 Participants |
| Severe Hepatically Impaired | Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (Frequency of Adverse Events, Serious Adverse Events, and Notable Laboratory Abnormalities) of of BAF312 After a Single Dose of BAF312 | At least one AE | 1 Participants |
| Severe Hepatically Impaired | Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (Frequency of Adverse Events, Serious Adverse Events, and Notable Laboratory Abnormalities) of of BAF312 After a Single Dose of BAF312 | Death | 0 Participants |
| Severe Hepatically Impaired | Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (Frequency of Adverse Events, Serious Adverse Events, and Notable Laboratory Abnormalities) of of BAF312 After a Single Dose of BAF312 | Serious Adverse Events | 0 Participants |
| Matched Healthy Subjects - Mild | Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (Frequency of Adverse Events, Serious Adverse Events, and Notable Laboratory Abnormalities) of of BAF312 After a Single Dose of BAF312 | Serious Adverse Events | 0 Participants |
| Matched Healthy Subjects - Mild | Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (Frequency of Adverse Events, Serious Adverse Events, and Notable Laboratory Abnormalities) of of BAF312 After a Single Dose of BAF312 | At least one AE | 1 Participants |
| Matched Healthy Subjects - Mild | Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (Frequency of Adverse Events, Serious Adverse Events, and Notable Laboratory Abnormalities) of of BAF312 After a Single Dose of BAF312 | Death | 0 Participants |