Hepatic Impairment
Conditions
Keywords
hepatic impairment
Brief summary
This is a study to characterize the pharmacokinetics as well as safety and tolerability of a single oral dose of LCZ696 200 mg in subjects with mild and moderate hepatic impairment compared to matched healthy subjects
Interventions
DRUGLCZ696
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* All subjects: * Male and female subjects aged 18-75 years. * Body weight at least 55 kg with a body mass index between 18-35 kg/m2. * Hepatic impairment subjects: * Mild or moderate hepatic impairment.
Exclusion criteria
* All subjects: * Clinical manifestations of postural symptomatic hypotension at screening or baseline. * History of hypersensitivity to LCZ696 or to drugs of similar classes. * Hepatic impairment subjects: * Hepatic impairment due to non-liver disease. * Treatment with any vasodilator, autonomic alpha blocker or beta2 agonist within 2 weeks of dosing. * Encephalopathyy Stage III or IV. * Primary biliary liver cirrhosis or biliary obstruction. * History of gastro-intestinal bleeding within 3 months prior to screening. * Healthy subjects: * Any surgical or medical condition which might significantly alter the distribution, or excretion of drugs, or which may jeopardize the subject in case of participation in the study. * Use of prescription drugs, herbal supplements, and/or over-the-counter medication, dietary supplements (vitamins included) within 2 weeks prior to initial dosing. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | From pre-dose on Day 1 until 96h post-dose (Day 5) | Blood samples were taken on Day 1 (treatment day) within 60 minutes prior to dosing, then, 0.5,1,1.5,2,3,4,6,8,12 hours after the dosing and on Days 2, 3, 4 and 5 post dosing |
| Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time [AUCinf)] of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | From pre-dose on Day 1 until 96h post-dose (Day 5) | Blood samples were taken on Day 1 (treatment day) within 60 minutes prior to dosing, then, 0.5,1,1.5,2,3,4,6,8,12 hours after the dosing and on Days 2, 3, 4 and 5 post dosing |
| Maximum Plasma Concentration (Cmax) for LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | From pre-dose on Day 1 until 96h post-dose (Day 5) | Blood samples were taken on Day 1 (treatment day) within 60 minutes prior to dosing, then, 0.5,1,1.5,2,3,4,6,8,12 hours after the dosing and on Days 2, 3, 4 and 5 post dosing |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events, Serious Adverse Events and Death | From the screening visit until Day 5 | Adverse events, serious adverse events and death were monitored from screening to end of study |
Countries
Germany
Participant flow
Recruitment details
Participants received the study treatment according to the population subset that was defined based on the severity of hepatic impairment and healthy volunteers: Group 1, subjects with mild hepatic impairment; Group 2, subjects with moderate hepatic impairment; Groups 3 and 4, healthy volunteers matching to Groups 1 and 2, respectively.
Participants by arm
| Arm | Count |
|---|---|
| Participants With Mild Hepatic Impairment (HI) LCZ696 200 mg, given as a single oral dose | 8 |
| Participants With Moderate Hepatic Impairment (HI) LCZ696 200 mg, given as a single oral dose | 8 |
| Healthy Volunteers (Mild HI Matched) LCZ696 200 mg, given as a single oral dose. Each healthy volunteer matched in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in group 1 | 8 |
| Healthy Volunteers (Moderate HI Matched) LCZ696 200 mg, given as a single oral dose. Each healthy volunteer matched in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in group 2 | 8 |
| Total | 32 |
Baseline characteristics
| Characteristic | Participants With Mild Hepatic Impairment (HI) | Participants With Moderate Hepatic Impairment (HI) | Healthy Volunteers (Mild HI Matched) | Healthy Volunteers (Moderate HI Matched) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 59.1 Years STANDARD_DEVIATION 7.92 | 57.9 Years STANDARD_DEVIATION 11.67 | 58.9 Years STANDARD_DEVIATION 8.68 | 60.3 Years STANDARD_DEVIATION 11.21 | 59.0 Years STANDARD_DEVIATION 9.54 |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 3 Participants | 1 Participants | 8 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 5 Participants | 7 Participants | 24 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 | 2 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time [AUCinf)] of LCZ696 Analytes (AHU377, LBQ657, and Valsartan)
Blood samples were taken on Day 1 (treatment day) within 60 minutes prior to dosing, then, 0.5,1,1.5,2,3,4,6,8,12 hours after the dosing and on Days 2, 3, 4 and 5 post dosing
Time frame: From pre-dose on Day 1 until 96h post-dose (Day 5)
Population: PK analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants With Mild Hepatic Impairment (HI) | Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time [AUCinf)] of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | AHU377 | 2540 ng*hr/mL | Standard Deviation 1010 |
| Participants With Mild Hepatic Impairment (HI) | Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time [AUCinf)] of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | LBQ657 | 121000 ng*hr/mL | Standard Deviation 41000 |
| Participants With Mild Hepatic Impairment (HI) | Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time [AUCinf)] of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | Valsartan | 28800 ng*hr/mL | Standard Deviation 16900 |
| Participants With Moderate Hepatic Impairment (HI) | Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time [AUCinf)] of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | LBQ657 | 187000 ng*hr/mL | Standard Deviation 124000 |
| Participants With Moderate Hepatic Impairment (HI) | Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time [AUCinf)] of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | AHU377 | 6200 ng*hr/mL | Standard Deviation 2980 |
| Participants With Moderate Hepatic Impairment (HI) | Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time [AUCinf)] of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | Valsartan | 65600 ng*hr/mL | Standard Deviation 50100 |
| Healthy Volunteers (Mild HI Matched) | Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time [AUCinf)] of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | LBQ657 | 78500 ng*hr/mL | Standard Deviation 14700 |
| Healthy Volunteers (Mild HI Matched) | Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time [AUCinf)] of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | Valsartan | 21900 ng*hr/mL | Standard Deviation 5950 |
| Healthy Volunteers (Mild HI Matched) | Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time [AUCinf)] of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | AHU377 | 1590 ng*hr/mL | Standard Deviation 390 |
| Healthy Volunteers (Moderate HI Matched) | Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time [AUCinf)] of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | Valsartan | 26500 ng*hr/mL | Standard Deviation 12400 |
| Healthy Volunteers (Moderate HI Matched) | Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time [AUCinf)] of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | LBQ657 | 84100 ng*hr/mL | Standard Deviation 14800 |
| Healthy Volunteers (Moderate HI Matched) | Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time [AUCinf)] of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | AHU377 | 1740 ng*hr/mL | Standard Deviation 519 |
Primary
Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LCZ696 Analytes (AHU377, LBQ657, and Valsartan)
Blood samples were taken on Day 1 (treatment day) within 60 minutes prior to dosing, then, 0.5,1,1.5,2,3,4,6,8,12 hours after the dosing and on Days 2, 3, 4 and 5 post dosing
Time frame: From pre-dose on Day 1 until 96h post-dose (Day 5)
Population: PK analysis set: The PK analysis set included all subjects with at least one available, valid (i.e. not flagged for exclusion) PK concentration measurement, who received any study drug, and experienced no protocol deviations with relevant impact on PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants With Mild Hepatic Impairment (HI) | Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | AHU377 | 2540 ng*hr/mL | Standard Deviation 1010 |
| Participants With Mild Hepatic Impairment (HI) | Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | Valsartan | 28500 ng*hr/mL | Standard Deviation 16900 |
| Participants With Mild Hepatic Impairment (HI) | Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | LBQ657 | 118000 ng*hr/mL | Standard Deviation 37000 |
| Participants With Moderate Hepatic Impairment (HI) | Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | AHU377 | 6200 ng*hr/mL | Standard Deviation 2970 |
| Participants With Moderate Hepatic Impairment (HI) | Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | Valsartan | 63800 ng*hr/mL | Standard Deviation 48700 |
| Participants With Moderate Hepatic Impairment (HI) | Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | LBQ657 | 173000 ng*hr/mL | Standard Deviation 99900 |
| Healthy Volunteers (Mild HI Matched) | Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | LBQ657 | 77900 ng*hr/mL | Standard Deviation 14700 |
| Healthy Volunteers (Mild HI Matched) | Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | AHU377 | 1580 ng*hr/mL | Standard Deviation 390 |
| Healthy Volunteers (Mild HI Matched) | Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | Valsartan | 21600 ng*hr/mL | Standard Deviation 5980 |
| Healthy Volunteers (Moderate HI Matched) | Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | AHU377 | 1740 ng*hr/mL | Standard Deviation 520 |
| Healthy Volunteers (Moderate HI Matched) | Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | Valsartan | 25300 ng*hr/mL | Standard Deviation 11800 |
| Healthy Volunteers (Moderate HI Matched) | Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | LBQ657 | 83100 ng*hr/mL | Standard Deviation 14700 |
Primary
Maximum Plasma Concentration (Cmax) for LCZ696 Analytes (AHU377, LBQ657, and Valsartan)
Blood samples were taken on Day 1 (treatment day) within 60 minutes prior to dosing, then, 0.5,1,1.5,2,3,4,6,8,12 hours after the dosing and on Days 2, 3, 4 and 5 post dosing
Time frame: From pre-dose on Day 1 until 96h post-dose (Day 5)
Population: PK analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants With Mild Hepatic Impairment (HI) | Maximum Plasma Concentration (Cmax) for LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | AHU377 | 2530 ng/mL | Standard Deviation 1400 |
| Participants With Mild Hepatic Impairment (HI) | Maximum Plasma Concentration (Cmax) for LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | LBQ657 | 7730 ng/mL | Standard Deviation 1470 |
| Participants With Mild Hepatic Impairment (HI) | Maximum Plasma Concentration (Cmax) for LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | Valsartan | 4000 ng/mL | Standard Deviation 2310 |
| Participants With Moderate Hepatic Impairment (HI) | Maximum Plasma Concentration (Cmax) for LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | Valsartan | 4180 ng/mL | Standard Deviation 2340 |
| Participants With Moderate Hepatic Impairment (HI) | Maximum Plasma Concentration (Cmax) for LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | LBQ657 | 6690 ng/mL | Standard Deviation 917 |
| Participants With Moderate Hepatic Impairment (HI) | Maximum Plasma Concentration (Cmax) for LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | AHU377 | 4430 ng/mL | Standard Deviation 1760 |
| Healthy Volunteers (Mild HI Matched) | Maximum Plasma Concentration (Cmax) for LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | AHU377 | 1510 ng/mL | Standard Deviation 585 |
| Healthy Volunteers (Mild HI Matched) | Maximum Plasma Concentration (Cmax) for LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | LBQ657 | 7450 ng/mL | Standard Deviation 1320 |
| Healthy Volunteers (Mild HI Matched) | Maximum Plasma Concentration (Cmax) for LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | Valsartan | 3880 ng/mL | Standard Deviation 1490 |
| Healthy Volunteers (Moderate HI Matched) | Maximum Plasma Concentration (Cmax) for LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | Valsartan | 3730 ng/mL | Standard Deviation 1540 |
| Healthy Volunteers (Moderate HI Matched) | Maximum Plasma Concentration (Cmax) for LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | AHU377 | 1410 ng/mL | Standard Deviation 445 |
| Healthy Volunteers (Moderate HI Matched) | Maximum Plasma Concentration (Cmax) for LCZ696 Analytes (AHU377, LBQ657, and Valsartan) | LBQ657 | 6770 ng/mL | Standard Deviation 1710 |
Secondary
Number of Participants With Adverse Events, Serious Adverse Events and Death
Adverse events, serious adverse events and death were monitored from screening to end of study
Time frame: From the screening visit until Day 5
Population: Safety set: The safety set includes all participants who received study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Participants With Mild Hepatic Impairment (HI) | Number of Participants With Adverse Events, Serious Adverse Events and Death | Adverse events (serious and non-serious) | 0 Participants |
| Participants With Mild Hepatic Impairment (HI) | Number of Participants With Adverse Events, Serious Adverse Events and Death | Serious adverse events | 0 Participants |
| Participants With Mild Hepatic Impairment (HI) | Number of Participants With Adverse Events, Serious Adverse Events and Death | Deaths | 0 Participants |
| Participants With Moderate Hepatic Impairment (HI) | Number of Participants With Adverse Events, Serious Adverse Events and Death | Adverse events (serious and non-serious) | 2 Participants |
| Participants With Moderate Hepatic Impairment (HI) | Number of Participants With Adverse Events, Serious Adverse Events and Death | Deaths | 0 Participants |
| Participants With Moderate Hepatic Impairment (HI) | Number of Participants With Adverse Events, Serious Adverse Events and Death | Serious adverse events | 0 Participants |
| Healthy Volunteers (Mild HI Matched) | Number of Participants With Adverse Events, Serious Adverse Events and Death | Deaths | 0 Participants |
| Healthy Volunteers (Mild HI Matched) | Number of Participants With Adverse Events, Serious Adverse Events and Death | Serious adverse events | 0 Participants |
| Healthy Volunteers (Mild HI Matched) | Number of Participants With Adverse Events, Serious Adverse Events and Death | Adverse events (serious and non-serious) | 0 Participants |
| Healthy Volunteers (Moderate HI Matched) | Number of Participants With Adverse Events, Serious Adverse Events and Death | Deaths | 0 Participants |
| Healthy Volunteers (Moderate HI Matched) | Number of Participants With Adverse Events, Serious Adverse Events and Death | Serious adverse events | 0 Participants |
| Healthy Volunteers (Moderate HI Matched) | Number of Participants With Adverse Events, Serious Adverse Events and Death | Adverse events (serious and non-serious) | 0 Participants |