Trial Outcomes & Findings for Study to Evaluate a Dose of Telotristat Etiprate in Male and Female With Mild, Moderate and Severe Hepatic Insufficiency and Matched Healthy Subjects (NCT NCT02683577)
NCT ID: NCT02683577
Last Updated: 2019-01-25
Results Overview
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.
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
24 participants
Primary outcome timeframe
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).
Results posted on
2019-01-25
Participant Flow
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).
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.
Participant milestones
| Measure |
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.
|
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.
|
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.
|
|---|---|---|---|
|
Overall Study
STARTED
|
8
|
8
|
8
|
|
Overall Study
COMPLETED
|
8
|
8
|
8
|
|
Overall Study
NOT COMPLETED
|
0
|
0
|
0
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Study to Evaluate a Dose of Telotristat Etiprate in Male and Female With Mild, Moderate and Severe Hepatic Insufficiency and Matched Healthy Subjects
Baseline characteristics by cohort
| Measure |
Healthy Control
n=8 Participants
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.
|
Mild HI
n=8 Participants
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.
|
Moderate HI
n=8 Participants
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.
|
Total Title
n=24 Participants
|
|---|---|---|---|---|
|
Age, Categorical
<=18 years
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
7 Participants
n=5 Participants
|
8 Participants
n=7 Participants
|
7 Participants
n=5 Participants
|
22 Participants
n=4 Participants
|
|
Age, Categorical
>=65 years
|
1 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
2 Participants
n=4 Participants
|
|
Sex: Female, Male
Female
|
3 Participants
n=5 Participants
|
4 Participants
n=7 Participants
|
3 Participants
n=5 Participants
|
10 Participants
n=4 Participants
|
|
Sex: Female, Male
Male
|
5 Participants
n=5 Participants
|
4 Participants
n=7 Participants
|
5 Participants
n=5 Participants
|
14 Participants
n=4 Participants
|
PRIMARY outcome
Timeframe: 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\[0-tlast\]).
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.
Outcome measures
| Measure |
Healthy Control
n=8 Participants
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.
|
Mild HI
n=8 Participants
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.
|
Moderate HI
n=7 Participants
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.
|
All HI
n=15 Participants
The all HI group represented all subjects in either HI group (mild + moderate). All subjects in each study group received a single oral dose of telotristat ethyl hippurate 500 mg (2x250 mg) on Day 1.
|
|---|---|---|---|---|
|
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
|
6.88 ng/mL
Geometric Coefficient of Variation 106.6
|
9.99 ng/mL
Geometric Coefficient of Variation 47.8
|
8.19 ng/mL
Geometric Coefficient of Variation 81.0
|
PRIMARY outcome
Timeframe: 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\[0-tlast\]).
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.
Outcome measures
| Measure |
Healthy Control
n=8 Participants
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.
|
Mild HI
n=8 Participants
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.
|
Moderate HI
n=7 Participants
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.
|
All HI
n=15 Participants
The all HI group represented all subjects in either HI group (mild + moderate). All subjects in each study group received a single oral dose of telotristat ethyl hippurate 500 mg (2x250 mg) on Day 1.
|
|---|---|---|---|---|
|
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
Interval 0.5 to 3.0
|
1.000 hour
Interval 0.5 to 3.0
|
1.000 hour
Interval 0.5 to 1.0
|
1.000 hour
Interval 0.5 to 3.0
|
PRIMARY outcome
Timeframe: 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\[0-tlast\]).
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.
Outcome measures
| Measure |
Healthy Control
n=8 Participants
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.
|
Mild HI
n=8 Participants
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.
|
Moderate HI
n=7 Participants
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.
|
All HI
n=15 Participants
The all HI group represented all subjects in either HI group (mild + moderate). All subjects in each study group received a single oral dose of telotristat ethyl hippurate 500 mg (2x250 mg) on Day 1.
|
|---|---|---|---|---|
|
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
|
11.33 ng*h/mL
Geometric Coefficient of Variation 100.5
|
15.65 ng*h/mL
Geometric Coefficient of Variation 62.7
|
13.17 ng*h/mL
Geometric Coefficient of Variation 82.5
|
PRIMARY outcome
Timeframe: 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.
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%.
Outcome measures
| Measure |
Healthy Control
n=3 Participants
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.
|
Mild HI
n=7 Participants
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.
|
Moderate HI
n=6 Participants
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.
|
All HI
n=13 Participants
The all HI group represented all subjects in either HI group (mild + moderate). All subjects in each study group received a single oral dose of telotristat ethyl hippurate 500 mg (2x250 mg) on Day 1.
|
|---|---|---|---|---|
|
Assessment of Area Under the Plasma Concentration Time Curve From Time 0 to Infinity (AUC[0-inf]) for Telotristat Ethyl
|
NA ng*h/mL
Geometric Coefficient of Variation NA
No descriptive statistics were computed when more than 1/3 of the PK parameter values were not determined.
|
11.70 ng*h/mL
Geometric Coefficient of Variation 108.4
|
17.79 ng*h/mL
Geometric Coefficient of Variation 58.5
|
14.20 ng*h/mL
Geometric Coefficient of Variation 86.5
|
PRIMARY outcome
Timeframe: 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\[0-tlast\]).
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.
Outcome measures
| Measure |
Healthy Control
n=8 Participants
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.
|
Mild HI
n=8 Participants
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.
|
Moderate HI
n=7 Participants
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.
|
All HI
n=15 Participants
The all HI group represented all subjects in either HI group (mild + moderate). All subjects in each study group received a single oral dose of telotristat ethyl hippurate 500 mg (2x250 mg) on Day 1.
|
|---|---|---|---|---|
|
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
|
1143.9 ng/mL
Geometric Coefficient of Variation 65.7
|
1333.3 ng/mL
Geometric Coefficient of Variation 25.2
|
1228.7 ng/mL
Geometric Coefficient of Variation 48.6
|
PRIMARY outcome
Timeframe: 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\[0-tlast\]).
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.
Outcome measures
| Measure |
Healthy Control
n=8 Participants
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.
|
Mild HI
n=8 Participants
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.
|
Moderate HI
n=7 Participants
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.
|
All HI
n=15 Participants
The all HI group represented all subjects in either HI group (mild + moderate). All subjects in each study group received a single oral dose of telotristat ethyl hippurate 500 mg (2x250 mg) on Day 1.
|
|---|---|---|---|---|
|
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
Interval 1.0 to 3.0
|
2.000 hour
Interval 2.0 to 3.0
|
2.000 hour
Interval 2.0 to 3.0
|
2.000 hour
Interval 2.0 to 3.0
|
PRIMARY outcome
Timeframe: 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\[0-tlast\]).
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.
Outcome measures
| Measure |
Healthy Control
n=8 Participants
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.
|
Mild HI
n=8 Participants
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.
|
Moderate HI
n=7 Participants
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.
|
All HI
n=15 Participants
The all HI group represented all subjects in either HI group (mild + moderate). All subjects in each study group received a single oral dose of telotristat ethyl hippurate 500 mg (2x250 mg) on Day 1.
|
|---|---|---|---|---|
|
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
|
5831.2 ng*h/mL
Geometric Coefficient of Variation 82.6
|
8565.4 ng*h/mL
Geometric Coefficient of Variation 45.5
|
6977.2 ng*h/mL
Geometric Coefficient of Variation 68.0
|
PRIMARY outcome
Timeframe: 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.
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%.
Outcome measures
| Measure |
Healthy Control
n=7 Participants
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.
|
Mild HI
n=8 Participants
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.
|
Moderate HI
n=7 Participants
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.
|
All HI
n=15 Participants
The all HI group represented all subjects in either HI group (mild + moderate). All subjects in each study group received a single oral dose of telotristat ethyl hippurate 500 mg (2x250 mg) on Day 1.
|
|---|---|---|---|---|
|
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
|
5866.5 ng*h/mL
Geometric Coefficient of Variation 82.3
|
8626.3 ng*h/mL
Geometric Coefficient of Variation 45.7
|
7022.9 ng*h/mL
Geometric Coefficient of Variation 67.9
|
PRIMARY outcome
Timeframe: 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.
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.
Outcome measures
| Measure |
Healthy Control
n=7 Participants
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.
|
Mild HI
n=8 Participants
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.
|
Moderate HI
n=7 Participants
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.
|
All HI
n=15 Participants
The all HI group represented all subjects in either HI group (mild + moderate). All subjects in each study group received a single oral dose of telotristat ethyl hippurate 500 mg (2x250 mg) on Day 1.
|
|---|---|---|---|---|
|
Assessment of t1/2 for Telotristat Ethyl and LP-778902 (Active Metabolite)
Telotristat ethyl
|
NA hour
Geometric Coefficient of Variation NA
No descriptive statistics were computed when more than 1/3 of the PK parameter values were not determined.
|
0.901 hour
Geometric Coefficient of Variation 31.1
|
1.002 hour
Geometric Coefficient of Variation 31.2
|
0.947 hour
Geometric Coefficient of Variation 30.3
|
|
Assessment of t1/2 for Telotristat Ethyl and LP-778902 (Active Metabolite)
LP-778902
|
9.12 hour
Geometric Coefficient of Variation 6.8
|
10.96 hour
Geometric Coefficient of Variation 12.7
|
11.08 hour
Geometric Coefficient of Variation 10.8
|
11.02 hour
Geometric Coefficient of Variation 11.5
|
PRIMARY outcome
Timeframe: 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.
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.
Outcome measures
| Measure |
Healthy Control
n=7 Participants
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.
|
Mild HI
n=8 Participants
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.
|
Moderate HI
n=7 Participants
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.
|
All HI
n=15 Participants
The all HI group represented all subjects in either HI group (mild + moderate). All subjects in each study group received a single oral dose of telotristat ethyl hippurate 500 mg (2x250 mg) on Day 1.
|
|---|---|---|---|---|
|
Assessment of Apparent Terminal Elimination Rate Constant (λz) for Telotristat Ethyl and LP-778902 (Active Metabolite)
Telotristat ethyl
|
NA hour^-1
Geometric Coefficient of Variation NA
No descriptive statistics were computed when more than 1/3 of the PK parameter values were not determined.
|
0.769 hour^-1
Geometric Coefficient of Variation 31.1
|
0.691 hour^-1
Geometric Coefficient of Variation 31.2
|
0.732 hour^-1
Geometric Coefficient of Variation 30.3
|
|
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
|
0.06 hour^-1
Geometric Coefficient of Variation 12.7
|
0.06 hour^-1
Geometric Coefficient of Variation 10.8
|
0.06 hour^-1
Geometric Coefficient of Variation 11.5
|
Adverse Events
Healthy Control
Serious events: 0 serious events
Other events: 3 other events
Deaths: 0 deaths
Mild HI
Serious events: 0 serious events
Other events: 2 other events
Deaths: 0 deaths
Moderate HI
Serious events: 0 serious events
Other events: 3 other events
Deaths: 0 deaths
All HI
Serious events: 0 serious events
Other events: 5 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Healthy Control
n=8 participants at risk
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.
|
Mild HI
n=8 participants at risk
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.
|
Moderate HI
n=8 participants at risk
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.
|
All HI
n=16 participants at risk
The all HI group represented all subjects in either HI group (mild + moderate). All subjects in each study group received a single oral dose of telotristat ethyl hippurate 500 mg (2x250 mg) on Day 1.
|
|---|---|---|---|---|
|
Gastrointestinal disorders
Diarrhoea
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
25.0%
2/8 • Number of events 2 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
12.5%
2/16 • Number of events 2 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
|
Gastrointestinal disorders
Abdominal pain
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
12.5%
1/8 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
6.2%
1/16 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
|
Gastrointestinal disorders
Abdominal pain upper
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
12.5%
1/8 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
6.2%
1/16 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
|
Gastrointestinal disorders
Flatulence
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
12.5%
1/8 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
6.2%
1/16 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
|
Gastrointestinal disorders
Nausea
|
12.5%
1/8 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/16 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
|
Gastrointestinal disorders
Toothache
|
12.5%
1/8 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/16 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
|
Gastrointestinal disorders
Vomiting
|
12.5%
1/8 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/16 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
|
Blood and lymphatic system disorders
Leukopenia
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
25.0%
2/8 • Number of events 2 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
12.5%
2/16 • Number of events 2 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
|
Blood and lymphatic system disorders
Neutropenia
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
12.5%
1/8 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
6.2%
1/16 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
|
Nervous system disorders
Headache
|
12.5%
1/8 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
12.5%
1/8 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
6.2%
1/16 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
|
Investigations
Neutrophil count decreased
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
12.5%
1/8 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
6.2%
1/16 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
12.5%
1/8 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
6.2%
1/16 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
|
Vascular disorders
Hypotension
|
12.5%
1/8 • Number of events 1 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/8 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
0.00%
0/16 • Up to 15 days (Day 1 to Day 15)
Adverse event (AE) data is reported for the safety population which corresponds to all subjects who received at least one dose of study medication (24 subjects overall). Data is reported as treatment-emergent AEs, defined as any AE occurring during the active phase of the study until the end of study or early discontinuation visit.
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee The PI will provide the sponsor with any results communications for public release at least 90 days prior to the planned submission for their review.
- Publication restrictions are in place
Restriction type: OTHER