Hepatic Impairment
Conditions
Brief summary
The purpose of the protocol is to assess the pharmacokinetics, safety and tolerability of a single dose of telotristat etiprate in subjects with various stages of hepatic impairment compared to healthy control subjects.
Interventions
Sponsors
Ipsen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Body mass index (BMI) between 18 and 34 kg/m², inclusive, at screening. BMI 35 may be accepted in case of 3-point scored ascites. * Minimum body weight of 50 kg. * Vital signs (after 5 minutes resting in a supine position) that are within study specified ranges * Female subjects of childbearing potential must agree to use an adequate double-barrier method of contraception during the study and for 30 days after discharge. * Subjects with impaired hepatic function: Clinical diagnosis of chronic hepatic disease (stable for more than 3 months) with a documented history of underlying hepatic insufficiency and no acute episodes of illness within 30 days prior to Day -1, and no significant change in disease status (ie, up to 1 point in the Child-Pugh classification) from screening to Day -1. * Control subjects with normal hepatic function: Clinical laboratory test results must be strictly within the normal laboratory reference ranges for liver function, and mean corpuscular volume (MCV) or, for other parameters, deemed as not clinically significant by the investigator.
Exclusion criteria
* Presence of clinically significant physical, laboratory, or Electrocardiogram (ECG) findings (with the exception of those parameters that are resulting from the underlying hepatic disease) that, in the opinion of the investigator, may interfere with any aspect of study conduct or interpretation of results. * Clinically significant illness or disease as determined by medical history, including cardiac, pulmonary, hepatic (other than reason for their hepatic impairment), biliary, Gastrointestinal (GI), endocrinologic, or renal disorders, or cancer within the last 5 years (except localised or in situ nonmelanoma skin cancer), physical examination, clinical laboratory tests, and 12-lead ECGs. * Receipt of any investigational agent or study drug within 30 days or 10 half-lives, whichever is longer, prior to dosing. * Smoking more than 20 cigarettes (eg, 1 pack) per day or equivalent (eg, e-vapour cigarette, pipe, cigar, chewing tobacco, nicotine patch, nicotine gum); unable or unwilling to refrain from smoking and tobacco use for 2 hours prior to dosing and 4 hours after dose administration. * History of any serious adverse reaction or hypersensitivity to any inactive component of telotristat etiprate (ie, microcrystalline cellulose, croscarmellose sodium (disintegrant), talc, silicon dioxide, and magnesium stearate (nonbovine)). * Existence of any surgical or medical condition that, in the judgment of the investigator and the sponsor's, medical monitor, might interfere with the absorption, distribution, metabolism, or excretion of telotristat etiprate. * History of any major surgery within 6 months or anticipated surgery prior to Day -1. * History of renal disease or significantly abnormal kidney function test. * History of any active infection within 30 days prior to Day 1, if deemed clinically significant by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Maximum Observed Plasma Drug Concentration (Cmax) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group | Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours [h] post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h). | Blood was sampled for the purpose of determining pharmacokinetic (PK) parameters for total telotristat ethyl using a validated, specific, and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical method. The method was selective, linear, precise and accurate within the range from 0.5 to 500 nanograms per millilitre (ng/mL) for telotristat ethyl and the lower limit of quantification (LoQ) was 0.5 ng/mL. Results were derived by non-compartmental analysis of the plasma concentration-time profiles. |
| Assessment of Time to Maximum Observed Plasma Concentration (Tmax) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group | Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h). | Blood was sampled for the purpose of determining PK parameters for total telotristat ethyl using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 0.5 to 500 ng/mL for telotristat ethyl and the LoQ was 0.5 ng/mL. Results were derived by non-compartmental analysis of the plasma concentration-time profiles. |
| Assessment of Area Under the Plasma Concentration Time Curve From 0 to Time t Corresponding to the Last Quantifiable Concentration (AUC[0-tlast]) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group | Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h). | Blood was sampled for the purpose of determining PK parameters for total telotristat ethyl using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 0.5 to 500 ng/mL for telotristat ethyl and the LoQ was 0.5 ng/mL. Results were derived by non-compartmental analysis of the plasma concentration-time profiles. |
| Assessment of Area Under the Plasma Concentration Time Curve From Time 0 to Infinity (AUC[0-inf]) for Telotristat Ethyl | Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h). | Blood was sampled for the purpose of determining PK parameters for total telotristat ethyl using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 0.5 to 500 ng/mL for telotristat ethyl and the LoQ was 0.5 ng/mL. Results were derived by non-compartmental analysis of the plasma concentration-time profiles. AUC(0-inf) was not determined when the apparent terminal elimination half-life (t1/2) could not be determined over a time interval equal to at least 2 times t1/2 and/or the adjusted coefficient of determination value was inferior to 0.7 and/or extrapolated AUC was greater than 20%. |
| Assessment of Cmax for LP-778902 (Active Metabolite) and Comparison Between Each HI Group and Healthy Control Group | Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h). | Blood was sampled for the purpose of determining PK parameters for LP-778902 (active metabolite of telotristat ethyl) using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 2 to 2000 ng/mL for LP-778902 and the LoQ was 2.0 ng/mL. Results were derived by non-compartmental analysis of the plasma concentration-time profiles. |
| Assessment of Tmax for LP-778902 (Active Metabolite) and Comparison Between Each Hepatic Impairment Group and Healthy Control Group and Comparison Between Each Hepatic Impairment Group and Healthy Control Group | Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h). | Blood was sampled for the purpose of determining PK parameters for LP-778902 (active metabolite of telotristat ethyl) using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 2 to 2000 ng/mL for LP-778902 and the LoQ was 2.0 ng/mL. Results were derived by non-compartmental analysis of the plasma concentration-time profiles. |
| Assessment of AUC(0-tlast) for LP-778902 (Active Metabolite) and Comparison Between Each Hepatic Impairment Group and Healthy Control Group | Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h). | Blood was sampled for the purpose of determining PK parameters for LP-778902 (active metabolite of telotristat ethyl) using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 2 to 2000 ng/mL for LP-778902 and the LoQ was 2.0 ng/mL. Results were derived by non-compartmental analysis of the plasma concentration-time profiles. |
| Assessment of AUC(0-inf) for LP-778902 (Active Metabolite) and Comparison Between Each HI Group and Healthy Control Group | Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h). | Blood was sampled for the purpose of determining PK parameters for LP-778902 (active metabolite of telotristat ethyl) using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 2 to 2000 ng/mL for LP-778902 and the LoQ was 2.0 ng/mL. Results were derived by non-compartmental analysis of the plasma concentration-time profiles. AUC(0-inf) was not determined when terminal half-life (t1/2) could not be determined over a time interval equal to at least 2 times t1/2 and/or the adjusted coefficient of determination value was inferior to 0.7 and/or extrapolated AUC was greater than 20%. |
| Assessment of t1/2 for Telotristat Ethyl and LP-778902 (Active Metabolite) | Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h). | Blood was sampled for the purpose of determining PK parameters for total telotristat ethyl and its active metabolite LP-778902 using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 0.5 to 500 ng/mL for telotristat ethyl and from 2 to 2000 ng/mL for LP-778902. The LoQ for telotristat ethyl and its metabolite LP-778902 were 0.5 ng/mL and 2.0 ng/mL, respectively. |
| Assessment of Apparent Terminal Elimination Rate Constant (λz) for Telotristat Ethyl and LP-778902 (Active Metabolite) | Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h). | Blood was sampled for the purpose of determining PK parameters for total telotristat ethyl and its active metabolite LP-778902 using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 0.5 to 500 ng/mL for telotristat ethyl and from 2 to 2000 ng/mL for LP-778902. The LoQ for telotristat ethyl and its metabolite LP-778902 were 0.5 ng/mL and 2.0 ng/mL, respectively. |
Countries
Moldova, Romania
Participant flow
Recruitment details
This was an open-label study conducted at 2 investigational sites, one in Romania and one in the Republic of Moldova. Subjects were enrolled to the study from 08 February 2016 (first subject enrolled) until 07 July 2016 (last subject completed).
Pre-assignment details
Subjects enrolled into 3 hepatic functional groups: * Healthy control subjects with normal hepatic function * Mild hepatic impairment (HI) subjects (Child-Pugh \[C-P\] class A) * Moderate HI subjects (C-P class B). C-P score was summed from 5 clinical assessments of liver disease; each measure scored 1-3, with 3 indicating most severe derangement.
Participants by arm
| Arm | Count |
|---|---|
| Healthy Control Subjects in the healthy control group were assessed as having normal hepatic function.
All subjects in each study group received a single oral dose of telotristat ethyl hippurate 500 mg (2x250 mg) on Day 1. | 8 |
| Mild HI Subjects in the mild HI group were assessed as C-P class A (5 to 6 points on C-P scale for classification of the severity of liver disease).
All subjects in each study group received a single oral dose of telotristat ethyl hippurate 500 mg (2x250 mg) on Day 1. | 8 |
| Moderate HI Subjects in the moderate HI group were assessed as C-P class B (7 to 9 points on C-P scale for classification of the severity of liver disease).
All subjects in each study group received a single oral dose of telotristat ethyl hippurate 500 mg (2x250 mg) on Day 1. | 8 |
| Total Title | 24 |
| Total | 48 |
Baseline characteristics
| Characteristic | Healthy Control | Mild HI | Moderate HI | Total Title |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 8 Participants | 7 Participants | 22 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 5 Participants | 14 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 | 3 / 8 | 2 / 8 | 3 / 8 | 5 / 16 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 16 |
Outcome results
Primary
Assessment of Apparent Terminal Elimination Rate Constant (λz) for Telotristat Ethyl and LP-778902 (Active Metabolite)
Blood was sampled for the purpose of determining PK parameters for total telotristat ethyl and its active metabolite LP-778902 using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 0.5 to 500 ng/mL for telotristat ethyl and from 2 to 2000 ng/mL for LP-778902. The LoQ for telotristat ethyl and its metabolite LP-778902 were 0.5 ng/mL and 2.0 ng/mL, respectively.
Time frame: Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h).
Population: The PK population corresponded to all subjects who received at least one dose of study medication, without protocol violation affecting PK evaluation and who had a sufficient number of plasma concentrations to estimate the main PK parameters (Cmax, Tmax and AUC\[0-tlast\]). Only subjects with data available for analysis are reported.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Control | Assessment of Apparent Terminal Elimination Rate Constant (λz) for Telotristat Ethyl and LP-778902 (Active Metabolite) | Telotristat ethyl | NA hour^-1 | — |
| Healthy Control | Assessment of Apparent Terminal Elimination Rate Constant (λz) for Telotristat Ethyl and LP-778902 (Active Metabolite) | LP-778902 | 0.08 hour^-1 | Geometric Coefficient of Variation 6.8 |
| Mild HI | Assessment of Apparent Terminal Elimination Rate Constant (λz) for Telotristat Ethyl and LP-778902 (Active Metabolite) | LP-778902 | 0.06 hour^-1 | Geometric Coefficient of Variation 12.7 |
| Mild HI | Assessment of Apparent Terminal Elimination Rate Constant (λz) for Telotristat Ethyl and LP-778902 (Active Metabolite) | Telotristat ethyl | 0.769 hour^-1 | Geometric Coefficient of Variation 31.1 |
| Moderate HI | Assessment of Apparent Terminal Elimination Rate Constant (λz) for Telotristat Ethyl and LP-778902 (Active Metabolite) | Telotristat ethyl | 0.691 hour^-1 | Geometric Coefficient of Variation 31.2 |
| Moderate HI | Assessment of Apparent Terminal Elimination Rate Constant (λz) for Telotristat Ethyl and LP-778902 (Active Metabolite) | LP-778902 | 0.06 hour^-1 | Geometric Coefficient of Variation 10.8 |
| All HI | Assessment of Apparent Terminal Elimination Rate Constant (λz) for Telotristat Ethyl and LP-778902 (Active Metabolite) | Telotristat ethyl | 0.732 hour^-1 | Geometric Coefficient of Variation 30.3 |
| All HI | Assessment of Apparent Terminal Elimination Rate Constant (λz) for Telotristat Ethyl and LP-778902 (Active Metabolite) | LP-778902 | 0.06 hour^-1 | Geometric Coefficient of Variation 11.5 |
Primary
Assessment of Area Under the Plasma Concentration Time Curve From 0 to Time t Corresponding to the Last Quantifiable Concentration (AUC[0-tlast]) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group
Blood was sampled for the purpose of determining PK parameters for total telotristat ethyl using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 0.5 to 500 ng/mL for telotristat ethyl and the LoQ was 0.5 ng/mL. Results were derived by non-compartmental analysis of the plasma concentration-time profiles.
Time frame: Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h).
Population: The PK population corresponded to all subjects who received at least one dose of study medication, without protocol violation affecting PK evaluation and who had a sufficient number of plasma concentrations to estimate the main PK parameters (Cmax, Tmax and AUC\[0-tlast\]).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Healthy Control | Assessment of Area Under the Plasma Concentration Time Curve From 0 to Time t Corresponding to the Last Quantifiable Concentration (AUC[0-tlast]) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group | 4.94 ng*h/mL | Geometric Coefficient of Variation 85.5 |
| Mild HI | Assessment of Area Under the Plasma Concentration Time Curve From 0 to Time t Corresponding to the Last Quantifiable Concentration (AUC[0-tlast]) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group | 11.33 ng*h/mL | Geometric Coefficient of Variation 100.5 |
| Moderate HI | Assessment of Area Under the Plasma Concentration Time Curve From 0 to Time t Corresponding to the Last Quantifiable Concentration (AUC[0-tlast]) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group | 15.65 ng*h/mL | Geometric Coefficient of Variation 62.7 |
| All HI | Assessment of Area Under the Plasma Concentration Time Curve From 0 to Time t Corresponding to the Last Quantifiable Concentration (AUC[0-tlast]) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group | 13.17 ng*h/mL | Geometric Coefficient of Variation 82.5 |
Comparison: Comparison of mild HI group (Test) versus healthy control group (Reference) for AUC(0-tlast) values for telotristat ethyl.90% CI: [1.144, 4.598]
Comparison: Comparison of moderate HI group (Test) versus healthy control group (Reference) on AUC(0-tlast) values for telotristat ethyl.90% CI: [1.715, 5.852]
Primary
Assessment of Area Under the Plasma Concentration Time Curve From Time 0 to Infinity (AUC[0-inf]) for Telotristat Ethyl
Blood was sampled for the purpose of determining PK parameters for total telotristat ethyl using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 0.5 to 500 ng/mL for telotristat ethyl and the LoQ was 0.5 ng/mL. Results were derived by non-compartmental analysis of the plasma concentration-time profiles. AUC(0-inf) was not determined when the apparent terminal elimination half-life (t1/2) could not be determined over a time interval equal to at least 2 times t1/2 and/or the adjusted coefficient of determination value was inferior to 0.7 and/or extrapolated AUC was greater than 20%.
Time frame: Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h).
Population: The PK population corresponded to all subjects who received at least one dose of study medication, without protocol violation affecting PK evaluation and who had a sufficient number of plasma concentrations to estimate the main PK parameters (Cmax, Tmax and AUC\[0-tlast\]). Only subjects with data available for analysis are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Healthy Control | Assessment of Area Under the Plasma Concentration Time Curve From Time 0 to Infinity (AUC[0-inf]) for Telotristat Ethyl | NA ng*h/mL | — |
| Mild HI | Assessment of Area Under the Plasma Concentration Time Curve From Time 0 to Infinity (AUC[0-inf]) for Telotristat Ethyl | 11.70 ng*h/mL | Geometric Coefficient of Variation 108.4 |
| Moderate HI | Assessment of Area Under the Plasma Concentration Time Curve From Time 0 to Infinity (AUC[0-inf]) for Telotristat Ethyl | 17.79 ng*h/mL | Geometric Coefficient of Variation 58.5 |
| All HI | Assessment of Area Under the Plasma Concentration Time Curve From Time 0 to Infinity (AUC[0-inf]) for Telotristat Ethyl | 14.20 ng*h/mL | Geometric Coefficient of Variation 86.5 |
Primary
Assessment of AUC(0-inf) for LP-778902 (Active Metabolite) and Comparison Between Each HI Group and Healthy Control Group
Blood was sampled for the purpose of determining PK parameters for LP-778902 (active metabolite of telotristat ethyl) using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 2 to 2000 ng/mL for LP-778902 and the LoQ was 2.0 ng/mL. Results were derived by non-compartmental analysis of the plasma concentration-time profiles. AUC(0-inf) was not determined when terminal half-life (t1/2) could not be determined over a time interval equal to at least 2 times t1/2 and/or the adjusted coefficient of determination value was inferior to 0.7 and/or extrapolated AUC was greater than 20%.
Time frame: Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h).
Population: The PK population corresponded to all subjects who received at least one dose of study medication, without protocol violation affecting PK evaluation and who had a sufficient number of plasma concentrations to estimate the main PK parameters (Cmax, Tmax and AUC\[0-tlast\]). Only subjects with data available for analysis are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Healthy Control | Assessment of AUC(0-inf) for LP-778902 (Active Metabolite) and Comparison Between Each HI Group and Healthy Control Group | 2599.0 ng*h/mL | Geometric Coefficient of Variation 34.2 |
| Mild HI | Assessment of AUC(0-inf) for LP-778902 (Active Metabolite) and Comparison Between Each HI Group and Healthy Control Group | 5866.5 ng*h/mL | Geometric Coefficient of Variation 82.3 |
| Moderate HI | Assessment of AUC(0-inf) for LP-778902 (Active Metabolite) and Comparison Between Each HI Group and Healthy Control Group | 8626.3 ng*h/mL | Geometric Coefficient of Variation 45.7 |
| All HI | Assessment of AUC(0-inf) for LP-778902 (Active Metabolite) and Comparison Between Each HI Group and Healthy Control Group | 7022.9 ng*h/mL | Geometric Coefficient of Variation 67.9 |
Comparison: Comparison of mild HI group (Test) versus healthy control group (Reference) on ln transformed AUC(0-inf) values for LP-778902.90% CI: [1.33, 3.82]
Comparison: Comparison of moderate HI group (Test) versus healthy control group (Reference) on AUC(0-inf) values for LP-778902.90% CI: [2.3, 4.8]
Primary
Assessment of AUC(0-tlast) for LP-778902 (Active Metabolite) and Comparison Between Each Hepatic Impairment Group and Healthy Control Group
Blood was sampled for the purpose of determining PK parameters for LP-778902 (active metabolite of telotristat ethyl) using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 2 to 2000 ng/mL for LP-778902 and the LoQ was 2.0 ng/mL. Results were derived by non-compartmental analysis of the plasma concentration-time profiles.
Time frame: Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h).
Population: The PK population corresponded to all subjects who received at least one dose of study medication, without protocol violation affecting PK evaluation and who had a sufficient number of plasma concentrations to estimate the main PK parameters (Cmax, Tmax and AUC\[0-tlast\]).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Healthy Control | Assessment of AUC(0-tlast) for LP-778902 (Active Metabolite) and Comparison Between Each Hepatic Impairment Group and Healthy Control Group | 2436.5 ng*h/mL | Geometric Coefficient of Variation 36.3 |
| Mild HI | Assessment of AUC(0-tlast) for LP-778902 (Active Metabolite) and Comparison Between Each Hepatic Impairment Group and Healthy Control Group | 5831.2 ng*h/mL | Geometric Coefficient of Variation 82.6 |
| Moderate HI | Assessment of AUC(0-tlast) for LP-778902 (Active Metabolite) and Comparison Between Each Hepatic Impairment Group and Healthy Control Group | 8565.4 ng*h/mL | Geometric Coefficient of Variation 45.5 |
| All HI | Assessment of AUC(0-tlast) for LP-778902 (Active Metabolite) and Comparison Between Each Hepatic Impairment Group and Healthy Control Group | 6977.2 ng*h/mL | Geometric Coefficient of Variation 68 |
Comparison: Comparison of mild HI group (Test) versus healthy control group (Reference) on AUC(0-tlast) values for LP-778902.90% CI: [1.45, 3.94]
Comparison: Comparison of moderate HI group (Test) versus healthy control group (Reference) on AUC(0-tlast) values for LP-778902.90% CI: [2.45, 5.03]
Primary
Assessment of Cmax for LP-778902 (Active Metabolite) and Comparison Between Each HI Group and Healthy Control Group
Blood was sampled for the purpose of determining PK parameters for LP-778902 (active metabolite of telotristat ethyl) using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 2 to 2000 ng/mL for LP-778902 and the LoQ was 2.0 ng/mL. Results were derived by non-compartmental analysis of the plasma concentration-time profiles.
Time frame: Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h).
Population: The PK population corresponded to all subjects who received at least one dose of study medication, without protocol violation affecting PK evaluation and who had a sufficient number of plasma concentrations to estimate the main PK parameters (Cmax, Tmax and AUC\[0-tlast\]).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Healthy Control | Assessment of Cmax for LP-778902 (Active Metabolite) and Comparison Between Each HI Group and Healthy Control Group | 666.1 ng/mL | Geometric Coefficient of Variation 36.4 |
| Mild HI | Assessment of Cmax for LP-778902 (Active Metabolite) and Comparison Between Each HI Group and Healthy Control Group | 1143.9 ng/mL | Geometric Coefficient of Variation 65.7 |
| Moderate HI | Assessment of Cmax for LP-778902 (Active Metabolite) and Comparison Between Each HI Group and Healthy Control Group | 1333.3 ng/mL | Geometric Coefficient of Variation 25.2 |
| All HI | Assessment of Cmax for LP-778902 (Active Metabolite) and Comparison Between Each HI Group and Healthy Control Group | 1228.7 ng/mL | Geometric Coefficient of Variation 48.6 |
Comparison: Comparison of mild HI group (Test) versus healthy control group (Reference) for Cmax values for LP-778902.90% CI: [1.11, 2.65]
Comparison: Comparison of moderate HI group (Test) versus healthy control group (Reference) on Cmax values for LP-778902.90% CI: [1.51, 2.66]
Primary
Assessment of Maximum Observed Plasma Drug Concentration (Cmax) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group
Blood was sampled for the purpose of determining pharmacokinetic (PK) parameters for total telotristat ethyl using a validated, specific, and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical method. The method was selective, linear, precise and accurate within the range from 0.5 to 500 nanograms per millilitre (ng/mL) for telotristat ethyl and the lower limit of quantification (LoQ) was 0.5 ng/mL. Results were derived by non-compartmental analysis of the plasma concentration-time profiles.
Time frame: Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours [h] post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h).
Population: The PK population (23 subjects overall) corresponded to all subjects who received at least one dose of study medication, without protocol violation affecting PK evaluation and who had a sufficient number of plasma concentrations to estimate the main PK parameters (Cmax, Tmax and AUC\[0-tlast\]).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Healthy Control | Assessment of Maximum Observed Plasma Drug Concentration (Cmax) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group | 4.06 ng/mL | Geometric Coefficient of Variation 54.4 |
| Mild HI | Assessment of Maximum Observed Plasma Drug Concentration (Cmax) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group | 6.88 ng/mL | Geometric Coefficient of Variation 106.6 |
| Moderate HI | Assessment of Maximum Observed Plasma Drug Concentration (Cmax) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group | 9.99 ng/mL | Geometric Coefficient of Variation 47.8 |
| All HI | Assessment of Maximum Observed Plasma Drug Concentration (Cmax) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group | 8.19 ng/mL | Geometric Coefficient of Variation 81 |
Comparison: Comparison of mild HI group (Test) versus healthy control group (Reference) for Cmax values for telotristat ethyl.90% CI: [0.904, 3.176]
Comparison: Comparison of moderate HI group (Test) versus healthy control group (Reference) for Cmax values for telotristat ethyl.90% CI: [1.579, 3.837]
Primary
Assessment of t1/2 for Telotristat Ethyl and LP-778902 (Active Metabolite)
Blood was sampled for the purpose of determining PK parameters for total telotristat ethyl and its active metabolite LP-778902 using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 0.5 to 500 ng/mL for telotristat ethyl and from 2 to 2000 ng/mL for LP-778902. The LoQ for telotristat ethyl and its metabolite LP-778902 were 0.5 ng/mL and 2.0 ng/mL, respectively.
Time frame: Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h).
Population: The PK population corresponded to all subjects who received at least one dose of study medication, without protocol violation affecting PK evaluation and who had a sufficient number of plasma concentrations to estimate the main PK parameters (Cmax, Tmax and AUC\[0-tlast\]). Only subjects with data available for analysis are reported.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Control | Assessment of t1/2 for Telotristat Ethyl and LP-778902 (Active Metabolite) | Telotristat ethyl | NA hour | — |
| Healthy Control | Assessment of t1/2 for Telotristat Ethyl and LP-778902 (Active Metabolite) | LP-778902 | 9.12 hour | Geometric Coefficient of Variation 6.8 |
| Mild HI | Assessment of t1/2 for Telotristat Ethyl and LP-778902 (Active Metabolite) | Telotristat ethyl | 0.901 hour | Geometric Coefficient of Variation 31.1 |
| Mild HI | Assessment of t1/2 for Telotristat Ethyl and LP-778902 (Active Metabolite) | LP-778902 | 10.96 hour | Geometric Coefficient of Variation 12.7 |
| Moderate HI | Assessment of t1/2 for Telotristat Ethyl and LP-778902 (Active Metabolite) | LP-778902 | 11.08 hour | Geometric Coefficient of Variation 10.8 |
| Moderate HI | Assessment of t1/2 for Telotristat Ethyl and LP-778902 (Active Metabolite) | Telotristat ethyl | 1.002 hour | Geometric Coefficient of Variation 31.2 |
| All HI | Assessment of t1/2 for Telotristat Ethyl and LP-778902 (Active Metabolite) | LP-778902 | 11.02 hour | Geometric Coefficient of Variation 11.5 |
| All HI | Assessment of t1/2 for Telotristat Ethyl and LP-778902 (Active Metabolite) | Telotristat ethyl | 0.947 hour | Geometric Coefficient of Variation 30.3 |
Primary
Assessment of Time to Maximum Observed Plasma Concentration (Tmax) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group
Blood was sampled for the purpose of determining PK parameters for total telotristat ethyl using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 0.5 to 500 ng/mL for telotristat ethyl and the LoQ was 0.5 ng/mL. Results were derived by non-compartmental analysis of the plasma concentration-time profiles.
Time frame: Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h).
Population: The PK population corresponded to all subjects who received at least one dose of study medication, without protocol violation affecting PK evaluation and who had a sufficient number of plasma concentrations to estimate the main PK parameters (Cmax, Tmax and AUC\[0-tlast\]).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Control | Assessment of Time to Maximum Observed Plasma Concentration (Tmax) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group | 1.000 hour |
| Mild HI | Assessment of Time to Maximum Observed Plasma Concentration (Tmax) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group | 1.000 hour |
| Moderate HI | Assessment of Time to Maximum Observed Plasma Concentration (Tmax) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group | 1.000 hour |
| All HI | Assessment of Time to Maximum Observed Plasma Concentration (Tmax) for Telotristat Ethyl and Comparison Between Each HI Group and Healthy Control Group | 1.000 hour |
Comparison: The Tmax was analysed using a non-parametric analysis (Walsh averages and appropriate quantile of the Wilcoxon signed rank test statistic). The median difference between the mild HI group (Test) versus healthy control group (Reference) and the corresponding 90% CIs were calculated by Hodges-Lehmann estimation.p-value: =190% CI: [0, 0]Wilcoxon (Mann-Whitney)
Comparison: The Tmax was analysed using a non-parametric analysis (Walsh averages and appropriate quantile of the Wilcoxon signed rank test statistic). The median difference between the moderate HI group (Test) versus healthy control group (Reference) and the corresponding 90% CIs were calculated by Hodges-Lehmann estimation.p-value: =190% CI: [0, 0]Wilcoxon (Mann-Whitney)
Primary
Assessment of Tmax for LP-778902 (Active Metabolite) and Comparison Between Each Hepatic Impairment Group and Healthy Control Group and Comparison Between Each Hepatic Impairment Group and Healthy Control Group
Blood was sampled for the purpose of determining PK parameters for LP-778902 (active metabolite of telotristat ethyl) using a LC-MS/MS bioanalytical method. The method was selective, linear, precise and accurate within the range from 2 to 2000 ng/mL for LP-778902 and the LoQ was 2.0 ng/mL. Results were derived by non-compartmental analysis of the plasma concentration-time profiles.
Time frame: Blood samples were collected on Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 h post-dose), Day 2 (24 h), Day 3 (48 h) and Day 4 (72 h).
Population: The PK population corresponded to all subjects who received at least one dose of study medication, without protocol violation affecting PK evaluation and who had a sufficient number of plasma concentrations to estimate the main PK parameters (Cmax, Tmax and AUC\[0-tlast\]).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Healthy Control | Assessment of Tmax for LP-778902 (Active Metabolite) and Comparison Between Each Hepatic Impairment Group and Healthy Control Group and Comparison Between Each Hepatic Impairment Group and Healthy Control Group | 2.000 hour |
| Mild HI | Assessment of Tmax for LP-778902 (Active Metabolite) and Comparison Between Each Hepatic Impairment Group and Healthy Control Group and Comparison Between Each Hepatic Impairment Group and Healthy Control Group | 2.000 hour |
| Moderate HI | Assessment of Tmax for LP-778902 (Active Metabolite) and Comparison Between Each Hepatic Impairment Group and Healthy Control Group and Comparison Between Each Hepatic Impairment Group and Healthy Control Group | 2.000 hour |
| All HI | Assessment of Tmax for LP-778902 (Active Metabolite) and Comparison Between Each Hepatic Impairment Group and Healthy Control Group and Comparison Between Each Hepatic Impairment Group and Healthy Control Group | 2.000 hour |
Comparison: The Tmax was analysed using a non-parametric analysis (Walsh averages and appropriate quantile of the Wilcoxon signed rank test statistic). The median differences between the hepatic impaired group (Test) versus the healthy control group (Reference) and the corresponding 90% CIs were calculated by Hodges-Lehmann estimation.p-value: =0.31690% CI: [0, 1]Wilcoxon (Mann-Whitney)
Comparison: The Tmax was analysed using a non-parametric analysis (Walsh averages and appropriate quantile of the Wilcoxon signed rank test statistic). The median differences between the hepatic impaired group (Test) versus the healthy control group (Reference) and the corresponding 90% CIs were calculated by Hodges-Lehmann estimation.p-value: =0.467190% CI: [0, 1]Wilcoxon (Mann-Whitney)