Adult Study Participants, Elderly Study Participants
Conditions
Keywords
Padsevonil, Phase 1, Pharmacokinetic
Brief summary
The purpose of the study is to evaluate the plasma pharmacokinetic of padsevonil in adult and elderly study participants.
Interventions
DRUGPadsevonil
Padsevonil will be administered in predefined dosages.
Sponsors
UCB Biopharma S.P.R.L.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Study participants in the adult cohort must be ≥18 to 64 years of age at the time of signing the informed consent form (ICF) * Study participants in the elderly cohort must be ≥65 years of age at the time of signing the ICF * Study participants who are overtly healthy as determined by medical evaluation, including medical history, physical examination, laboratory tests, and cardiac monitoring. In addition, elderly study participants must be considered to be in general good physical and mental health * Study participants must have a body weight of at least 50 kg for males and 45 kg for females, and a body mass index within the range of 18 to 32 kg/m2 (inclusive)
Exclusion criteria
* Study participant has a current or past psychiatric condition that, in the opinion of the Investigator, could compromise the study participant's safety or ability to participate in this study, or a history of schizophrenia or other psychotic disorder, bipolar disorder, or severe unipolar depression. The presence of potential psychiatric
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Area Under the Curve (AUCtau) Over a Dosing Interval of Multiple Doses Padsevonil (PSL) | Plasma samples were taken predose and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8 and 12 hours on Day 13 | AUCtau was measured in hours times nanograms per milliliter (h\*ng/mL). |
| The Maximum Plasma Concentration (Cmax) of a Single Dose Padsevonil (PSL) | Plasma samples were taken predose on Day 1 and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8, 12, 24, 48 and 72 hours postdose | Cmax was measured in nanograms per milliliter (ng/mL). |
| The Area Under the Curve From 0 to t (AUC0-t) of a Single Dose Padsevonil (PSL) | Plasma samples were taken predose on Day 1 and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8, 12, 24, 48 and 72 hours postdose | AUC0-t: area under the plasma concentration-time curve from time 0 to the last quantifiable concentration. It was measured in hours times nanograms per milliliter (h\*ng/mL). |
| The Area Under the Curve (AUC) of a Single Dose Padsevonil (PSL) | Plasma samples were taken predose on Day 1 and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8, 12, 24, 48 and 72 hours postdose | AUC was measured in hours times nanograms per milliliter (h\*ng/mL). |
| The Maximum Plasma Concentration at Steady-state (Cmax, ss) of Multiple Doses Padsevonil (PSL) | Plasma samples were taken predose and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8 and 12 hours on Day 13 | Cmax, ss was measured in nanograms per milliliter (ng/mL). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Amount of Padsevonil (PSL) Excreted in Urine | Urine samples were taken on Day 1, Day 2, Day 3, Day 4 and Day 13 | Samples were taken to assess the amount of padsevonil that was excreted in urine. Ae,ss refers to cumulative amount of PSL excreted in the urine at steady state. |
| The Ratio of Padsevonil (PSL) to Its Metabolites Excreted in Urine | Urine samples were taken on Day 1, Day 2, Day 3, Day 4 and Day 13 | Samples were taken to assess the metabolic ratio of padsevonil that was excreted in urine. MRAe was defined as the metabolic ratio of PSL to its metabolites for cumulative amount of PSL metabolites excreted in the urine. ss refers to steady state. |
| Number of Participants With Treatment-emergent Adverse Events | From Baseline until End-of-Treatment visit (up to Day 22) | An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study medication, whether or not considered related to the study medication. An AE could, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study medication. |
| Number of Participants With Serious Adverse Events | From Baseline until End-of-Treatment visit (up to Day 22) | A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: * Results in death * Is life-threatening * Requires in patient hospitalization or prolongation of existing hospitalization * Is a congenital anomaly or birth defect * Is an infection that requires treatment parenteral antibiotics * Other important medical events which based on medical or scientific judgement may jeopardize the patients, or may require medical or surgical intervention to prevent any of the above |
| Number of Participants With Treatment-emergent Adverse Events Leading to Discontinuation of the Study | From Baseline until End-of-Treatment visit (up to Day 22) | An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. |
Countries
United States
Participant flow
Recruitment details
The study started to enroll patients in July 2019 and concluded in October 2019.
Pre-assignment details
The study included a 28 days Screening period, a 21 days Treatment period: Period 1A single dose (SD) on Days 1 to 7 and Period 1B multiple dose (MD) on Days 8 to 21 and a Safety Follow-up period on Day 22. Participant Flow refers to the Full Analysis Set.
Participants by arm
| Arm | Count |
|---|---|
| Adults (18-64 Years) Participants received assigned single and multiple doses of padsevonil. | 10 |
| Elderly (>= 65 Years) Participants received assigned single and multiple doses of padsevonil. | 18 |
| Total Title | 28 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Adults (18-64 Years) | Elderly (>= 65 Years) | Total Title |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 18 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 0 Participants | 10 Participants |
| Age, Continuous | 44.4 years STANDARD_DEVIATION 10.2 | 69.7 years STANDARD_DEVIATION 4.5 | 60.6 years STANDARD_DEVIATION 14.1 |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 9 Participants | 18 Participants | 27 Participants |
| Sex: Female, Male Female | 6 Participants | 9 Participants | 15 Participants |
| Sex: Female, Male Male | 4 Participants | 9 Participants | 13 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 | 0 / 10 | 0 / 18 | 0 / 10 | 0 / 18 |
| other Total, other adverse events | 10 / 10 | 18 / 18 | 10 / 10 | 17 / 18 |
| serious Total, serious adverse events | 0 / 10 | 0 / 18 | 0 / 10 | 0 / 18 |
Outcome results
Primary
The Area Under the Curve (AUC) of a Single Dose Padsevonil (PSL)
AUC was measured in hours times nanograms per milliliter (h\*ng/mL).
Time frame: Plasma samples were taken predose on Day 1 and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8, 12, 24, 48 and 72 hours postdose
Population: The Pharmacokinetic-Per Protocol Set (PK-PPS) was a subset of the FAS, consisting of study participants who had no important protocol deviation (IPD) affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Adults (18-64 Years) (PK-PPS) | The Area Under the Curve (AUC) of a Single Dose Padsevonil (PSL) | 4950 h*ng/mL |
| Elderly (>= 65 Years) (PK-PPS) | The Area Under the Curve (AUC) of a Single Dose Padsevonil (PSL) | 6061 h*ng/mL |
Comparison: The ANOVA model included the fixed effects of age group. The natural logs were taken of the dependent variables and back-transformed after the analysis.90% CI: [0.893, 1.68]ANOVA
Primary
The Area Under the Curve (AUCtau) Over a Dosing Interval of Multiple Doses Padsevonil (PSL)
AUCtau was measured in hours times nanograms per milliliter (h\*ng/mL).
Time frame: Plasma samples were taken predose and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8 and 12 hours on Day 13
Population: The PK-PPS was a subset of the FAS, consisting of study participants who had no IPD affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. 1 participant in the adult cohort discontinued due to a TEAE after 5 days of PSL administration in the MD Period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Adults (18-64 Years) (PK-PPS) | The Area Under the Curve (AUCtau) Over a Dosing Interval of Multiple Doses Padsevonil (PSL) | 5346 h*ng/mL |
| Elderly (>= 65 Years) (PK-PPS) | The Area Under the Curve (AUCtau) Over a Dosing Interval of Multiple Doses Padsevonil (PSL) | 6307 h*ng/mL |
Comparison: The ANOVA model included the fixed effects of age group. The natural logs were taken of the dependent variables and back-transformed after the analysis.90% CI: [0.908, 1.53]ANOVA
Primary
The Area Under the Curve From 0 to t (AUC0-t) of a Single Dose Padsevonil (PSL)
AUC0-t: area under the plasma concentration-time curve from time 0 to the last quantifiable concentration. It was measured in hours times nanograms per milliliter (h\*ng/mL).
Time frame: Plasma samples were taken predose on Day 1 and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8, 12, 24, 48 and 72 hours postdose
Population: The Pharmacokinetic-Per Protocol Set (PK-PPS) was a subset of the FAS, consisting of study participants who had no important protocol deviation (IPD) affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Adults (18-64 Years) (PK-PPS) | The Area Under the Curve From 0 to t (AUC0-t) of a Single Dose Padsevonil (PSL) | 4915 h*ng/mL |
| Elderly (>= 65 Years) (PK-PPS) | The Area Under the Curve From 0 to t (AUC0-t) of a Single Dose Padsevonil (PSL) | 6011 h*ng/mL |
Comparison: The ANOVA model included the fixed effects of age group. The natural logs were taken of the dependent variables and back-transformed after the analysis.90% CI: [0.894, 1.67]ANOVA
Primary
The Maximum Plasma Concentration at Steady-state (Cmax, ss) of Multiple Doses Padsevonil (PSL)
Cmax, ss was measured in nanograms per milliliter (ng/mL).
Time frame: Plasma samples were taken predose and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8 and 12 hours on Day 13
Population: The PK-PPS was a subset of the FAS, consisting of study participants who had no IPD affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. 1 participant in the adult cohort discontinued due to a treatment emergent adverse event (TEAE) after 5 days of PSL administration in the MD Period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Adults (18-64 Years) (PK-PPS) | The Maximum Plasma Concentration at Steady-state (Cmax, ss) of Multiple Doses Padsevonil (PSL) | 1157 ng/mL |
| Elderly (>= 65 Years) (PK-PPS) | The Maximum Plasma Concentration at Steady-state (Cmax, ss) of Multiple Doses Padsevonil (PSL) | 1180 ng/mL |
Comparison: The ANOVA model included the fixed effects of age group. The natural logs were taken of the dependent variables and back-transformed after the analysis.90% CI: [0.829, 1.26]ANOVA
Primary
The Maximum Plasma Concentration (Cmax) of a Single Dose Padsevonil (PSL)
Cmax was measured in nanograms per milliliter (ng/mL).
Time frame: Plasma samples were taken predose on Day 1 and 0.25, 0.5, 0.75, 1, 1.5, 3, 4, 6, 8, 12, 24, 48 and 72 hours postdose
Population: The Pharmacokinetic-Per Protocol Set (PK-PPS) was a subset of the FAS, consisting of study participants who had no important protocol deviation (IPD) affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Adults (18-64 Years) (PK-PPS) | The Maximum Plasma Concentration (Cmax) of a Single Dose Padsevonil (PSL) | 903.6 ng/mL |
| Elderly (>= 65 Years) (PK-PPS) | The Maximum Plasma Concentration (Cmax) of a Single Dose Padsevonil (PSL) | 838.4 ng/mL |
Comparison: The analysis of variance (ANOVA) model included the fixed effects of age group. The natural logs were taken of the dependent variables and back-transformed after the analysis.90% CI: [0.725, 1.19]ANOVA
Secondary
Number of Participants With Serious Adverse Events
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: * Results in death * Is life-threatening * Requires in patient hospitalization or prolongation of existing hospitalization * Is a congenital anomaly or birth defect * Is an infection that requires treatment parenteral antibiotics * Other important medical events which based on medical or scientific judgement may jeopardize the patients, or may require medical or surgical intervention to prevent any of the above
Time frame: From Baseline until End-of-Treatment visit (up to Day 22)
Population: The Full Analysis Set (FAS) consisted of all study participants who signed the informed consent form (ICF) and received at least 1 dose of PSL.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Adults (18-64 Years) (PK-PPS) | Number of Participants With Serious Adverse Events | Single Dose Period (1A) | 0 Participants |
| Adults (18-64 Years) (PK-PPS) | Number of Participants With Serious Adverse Events | Multiple Dose Period (1B) | 0 Participants |
| Elderly (>= 65 Years) (PK-PPS) | Number of Participants With Serious Adverse Events | Multiple Dose Period (1B) | 0 Participants |
| Elderly (>= 65 Years) (PK-PPS) | Number of Participants With Serious Adverse Events | Single Dose Period (1A) | 0 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study medication, whether or not considered related to the study medication. An AE could, therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study medication.
Time frame: From Baseline until End-of-Treatment visit (up to Day 22)
Population: The Full Analysis Set (FAS) consisted of all study participants who signed the informed consent form (ICF) and received at least 1 dose of PSL.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Adults (18-64 Years) (PK-PPS) | Number of Participants With Treatment-emergent Adverse Events | Single Dose Period (1A) | 10 Participants |
| Adults (18-64 Years) (PK-PPS) | Number of Participants With Treatment-emergent Adverse Events | Multiple Dose Period (1B) | 10 Participants |
| Elderly (>= 65 Years) (PK-PPS) | Number of Participants With Treatment-emergent Adverse Events | Single Dose Period (1A) | 18 Participants |
| Elderly (>= 65 Years) (PK-PPS) | Number of Participants With Treatment-emergent Adverse Events | Multiple Dose Period (1B) | 17 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events Leading to Discontinuation of the Study
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Time frame: From Baseline until End-of-Treatment visit (up to Day 22)
Population: The Full Analysis Set (FAS) consisted of all study participants who signed the informed consent form (ICF) and received at least 1 dose of PSL.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Adults (18-64 Years) (PK-PPS) | Number of Participants With Treatment-emergent Adverse Events Leading to Discontinuation of the Study | Single Dose Period (1A) | 0 Participants |
| Adults (18-64 Years) (PK-PPS) | Number of Participants With Treatment-emergent Adverse Events Leading to Discontinuation of the Study | Multiple Dose Period (1B) | 1 Participants |
| Elderly (>= 65 Years) (PK-PPS) | Number of Participants With Treatment-emergent Adverse Events Leading to Discontinuation of the Study | Single Dose Period (1A) | 0 Participants |
| Elderly (>= 65 Years) (PK-PPS) | Number of Participants With Treatment-emergent Adverse Events Leading to Discontinuation of the Study | Multiple Dose Period (1B) | 0 Participants |
Secondary
The Amount of Padsevonil (PSL) Excreted in Urine
Samples were taken to assess the amount of padsevonil that was excreted in urine. Ae,ss refers to cumulative amount of PSL excreted in the urine at steady state.
Time frame: Urine samples were taken on Day 1, Day 2, Day 3, Day 4 and Day 13
Population: The Pharmacokinetic-Per Protocol Set (PK-PPS) was a subset of the FAS, consisting of study participants who had no important protocol deviation (IPD) affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adults (18-64 Years) (PK-PPS) | The Amount of Padsevonil (PSL) Excreted in Urine | Single dose: Day 1 (Ae) | 0.0862 milligrams | Geometric Coefficient of Variation 153.9 |
| Adults (18-64 Years) (PK-PPS) | The Amount of Padsevonil (PSL) Excreted in Urine | Multiple dose: Day 13 (Ae,ss) | 0.0924 milligrams | Geometric Coefficient of Variation 109.5 |
| Adults (18-64 Years) (PK-PPS) | The Amount of Padsevonil (PSL) Excreted in Urine | Metabolite 1, Single dose: Day 1 (Ae) | 0.941 milligrams | Geometric Coefficient of Variation 79.9 |
| Adults (18-64 Years) (PK-PPS) | The Amount of Padsevonil (PSL) Excreted in Urine | Metabolite 1, Multiple dose: Day 13 (Ae,ss) | 1.16 milligrams | Geometric Coefficient of Variation 96.9 |
| Adults (18-64 Years) (PK-PPS) | The Amount of Padsevonil (PSL) Excreted in Urine | Metabolite 2, Single dose: Day 1 (Ae) | 18.7 milligrams | Geometric Coefficient of Variation 68.3 |
| Adults (18-64 Years) (PK-PPS) | The Amount of Padsevonil (PSL) Excreted in Urine | Metabolite 2, Multiple dose: Day 13 (Ae,ss) | 13.3 milligrams | Geometric Coefficient of Variation 79.5 |
| Elderly (>= 65 Years) (PK-PPS) | The Amount of Padsevonil (PSL) Excreted in Urine | Metabolite 2, Single dose: Day 1 (Ae) | 14.6 milligrams | Geometric Coefficient of Variation 54.2 |
| Elderly (>= 65 Years) (PK-PPS) | The Amount of Padsevonil (PSL) Excreted in Urine | Single dose: Day 1 (Ae) | 0.0979 milligrams | Geometric Coefficient of Variation 45.9 |
| Elderly (>= 65 Years) (PK-PPS) | The Amount of Padsevonil (PSL) Excreted in Urine | Metabolite 1, Multiple dose: Day 13 (Ae,ss) | 1.86 milligrams | Geometric Coefficient of Variation 35.9 |
| Elderly (>= 65 Years) (PK-PPS) | The Amount of Padsevonil (PSL) Excreted in Urine | Multiple dose: Day 13 (Ae,ss) | 0.166 milligrams | Geometric Coefficient of Variation 45.5 |
| Elderly (>= 65 Years) (PK-PPS) | The Amount of Padsevonil (PSL) Excreted in Urine | Metabolite 2, Multiple dose: Day 13 (Ae,ss) | 14.4 milligrams | Geometric Coefficient of Variation 45.9 |
| Elderly (>= 65 Years) (PK-PPS) | The Amount of Padsevonil (PSL) Excreted in Urine | Metabolite 1, Single dose: Day 1 (Ae) | 1.13 milligrams | Geometric Coefficient of Variation 20.3 |
Secondary
The Ratio of Padsevonil (PSL) to Its Metabolites Excreted in Urine
Samples were taken to assess the metabolic ratio of padsevonil that was excreted in urine. MRAe was defined as the metabolic ratio of PSL to its metabolites for cumulative amount of PSL metabolites excreted in the urine. ss refers to steady state.
Time frame: Urine samples were taken on Day 1, Day 2, Day 3, Day 4 and Day 13
Population: The Pharmacokinetic-Per Protocol Set (PK-PPS) was a subset of the FAS, consisting of study participants who had no important protocol deviation (IPD) affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adults (18-64 Years) (PK-PPS) | The Ratio of Padsevonil (PSL) to Its Metabolites Excreted in Urine | Metabolite 1, Single dose: Day 1 (MRAe) | 10.6 ratio | Geometric Coefficient of Variation 52.8 |
| Adults (18-64 Years) (PK-PPS) | The Ratio of Padsevonil (PSL) to Its Metabolites Excreted in Urine | Metabolite 2, Single dose: Day 1 (MRAe) | 217 ratio | Geometric Coefficient of Variation 122.3 |
| Adults (18-64 Years) (PK-PPS) | The Ratio of Padsevonil (PSL) to Its Metabolites Excreted in Urine | Metabolite 1, Multiple dose: Day 13 (MRAe,ss) | 12.2 ratio | Geometric Coefficient of Variation 43.9 |
| Adults (18-64 Years) (PK-PPS) | The Ratio of Padsevonil (PSL) to Its Metabolites Excreted in Urine | Metabolite 2, Multiple dose: Day 13 (MRAe,ss) | 144 ratio | Geometric Coefficient of Variation 81.1 |
| Elderly (>= 65 Years) (PK-PPS) | The Ratio of Padsevonil (PSL) to Its Metabolites Excreted in Urine | Metabolite 2, Multiple dose: Day 13 (MRAe,ss) | 86.8 ratio | Geometric Coefficient of Variation 67.7 |
| Elderly (>= 65 Years) (PK-PPS) | The Ratio of Padsevonil (PSL) to Its Metabolites Excreted in Urine | Metabolite 1, Single dose: Day 1 (MRAe) | 11.2 ratio | Geometric Coefficient of Variation 40.3 |
| Elderly (>= 65 Years) (PK-PPS) | The Ratio of Padsevonil (PSL) to Its Metabolites Excreted in Urine | Metabolite 1, Multiple dose: Day 13 (MRAe,ss) | 10.9 ratio | Geometric Coefficient of Variation 38.2 |
| Elderly (>= 65 Years) (PK-PPS) | The Ratio of Padsevonil (PSL) to Its Metabolites Excreted in Urine | Metabolite 2, Single dose: Day 1 (MRAe) | 149 ratio | Geometric Coefficient of Variation 81.8 |