Effect of Atorvastatin on the Pharmacokinetics of Lomitapide
Conditions
Brief summary
The primary objective of this study is to assess the effect of atorvastatin, a weak cytochrome P450 (CYP) 3A4 inhibitor, on the pharmacokinetics (PK) of lomitapide and its 2 primary metabolites, M1 and M3.
Detailed description
This study will be a single center, randomized, open-label, 2-arm study to evaluate the effects of atorvastatin, a weak CYP3A4 inhibitor, on the PK of lomitapide in healthy male and female subjects when atorvastatin is administered simultaneously with lomitapide and when it is administered 12 hours after lomitapide.
Interventions
DRUGlomitapide
20 mg dose
DRUGAtorvastatin
80 mg
Sponsors
Aegerion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy males and females, between 18 and 55 years of age inclusive 2. BMI between 18.5 and 32.0 kg/m2, inclusive; total body weight of \>110 lbs (50 kg); 3. in good health, determined by no clinically significant or relevant abnormalities identified by a detailed medical history and medical exam 4. creatine phosphokinase, AST, and ALT levels must be below 1.5 times the upper limit of normal 5. clinical laboratory evaluations within the reference range for the test laboratory 6. negative test for selected drugs of abuse 7. negative hepatitis panel and negative HIV antibody screens 8. males will either be sterile or agree to use approved methods of contraception 9. all females must have a negative serum beta human chorionic gonadotropin pregnancy test and will be required to use a medically acceptable method of contraception. 10. able to comprehend and willing to sign an Informed Consent Form
Exclusion criteria
1. significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, GI, neurological, or psychiatric disorder 2. history of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance 3. history of stomach or intestinal surgery or resection 4. history of Gilbert's Syndrome or suspicion of Gilbert's Syndrome 5. subjects who have an abnormality in the 12-lead ECG 6. use of any drugs of abuse for 6 months prior to Check-in; 7. subjects who consume more than 14 units of alcohol per week or who have a significant history of alcoholism or drug/chemical abuse within 1 year prior to Check-in 8. use of any tobacco- or nicotine-containing products within 6 months prior to Check-in; 9. participation in any other investigational study drug trial within 30 days prior to Check-in; 10. use of any prescription medications/products within 14 days prior to Check-in unless deemed acceptable by the Investigator and Sponsor 11. use of any over-the-counter, nonprescription preparations within 7 days prior to Check-in, unless deemed acceptable by the Investigator and Sponsor 12. use of alcohol-, grapefruit- (including star fruit), or caffeine-containing foods or beverages within 72 hours prior to Check-in and through Study Completion 13. poor peripheral venous access; 14. donation of blood (500 mL) from 30 days prior to Screening through Study Completion 15. receipt of blood products within 2 months prior to Check-in; 16. any acute or chronic condition, scheduled hospitalization (inclusive of elective surgery during study) or scheduled travel prior to completion of all study procedures which, in the opinion of the Investigator, would limit the subject's ability to complete and/or participate in this clinical study; 17. subjects who, in the opinion of the Investigator, should not participate in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax | Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing | Maximum observed plasma concentration of lomitapide and its 2 primary metabolites (M1 & M3), following administration of lomitapide alone and coadministered with atorvastatin simultaneously (Arm 1) |
| Tmax | Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing | Time to reach maximum observed plasma concentration of lomitapide and its 2 primary metabolites (M1 & M3), following administration of lomitapide alone and coadministered with atorvastatin simultaneously (Arm 1) |
| AUC0-t | Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing | Area under the concentration-time curve from zero to the last quantifiable concentration of lomitapide and its 2 primary metabolites (M1 & M3), following administration of lomitapide alone and coadministered with atorvastatin simultaneously (Arm 1) |
| AUC0-∞ | Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing | Area under the concentration-time curve from zero to infinity of lomitapide and its 2 primary metabolites (M1 & M3), following administration of lomitapide alone and coadministered with atorvastatin simultaneously (Arm 1) |
| t1/2 | Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing | Apparent terminal elimination half-life of lomitapide and its 2 primary metabolites (M1 & M3), following administration of lomitapide alone and coadministered with atorvastatin simultaneously (Arm 1) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax | Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing | Maximum observed plasma concentration of lomitapide and its 2 primary metabolites (M1 & M3) following administration of lomitapide alone and coadministered with atorvastatin 12 hours apart (Arm 2) |
| Tmax | Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing | Time to reach maximum observed plasma concentration of lomitapide and its 2 primary metabolites (M1 & M3) following administration of lomitapide alone and coadministered with atorvastatin 12 hours apart (Arm 2) |
| AUC0-t | Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing | Area under the concentration-time curve from zero to the last quantifiable concentration of lomitapide and its 2 primary metabolites (M1 & M3) following administration of lomitapide alone and coadministered with atorvastatin 12 hours apart (Arm 2) |
| AUC0-∞ | Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing | Area under the concentration-time curve from zero to infinity of lomitapide and its 2 primary metabolites (M1 & M3) following administration of lomitapide alone and coadministered with atorvastatin 12 hours apart (Arm 2) |
| t1/2 | Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing | Apparent terminal elimination half-life of lomitapide and its 2 primary metabolites (M1 & M3) following administration of lomitapide alone and coadministered with atorvastatin 12 hours apart (Arm 2) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lomitapide & Atorvastatin - Taken Together 2 single oral doses of lomitapide (20 mg) with a 14-day washout between (Day 1 & Day 15)
11 single oral doses of atorvastatin (80 mg) (Day 11 through day 21)
lomitapide: 20 mg dose
Atorvastatin: 80 mg | 16 |
| Lomitapide & Atorvastatin - Approx. 12 Hours Between 2 single oral doses of lomitapide (20 mg) with a 14-day washout between (Day 1 & Day 15)
11 single oral doses of atorvastatin (80 mg) (Day 12 through day 22)
lomitapide: 20 mg dose
Atorvastatin: 80 mg | 16 |
| Total | 32 |
Baseline characteristics
| Characteristic | Lomitapide & Atorvastatin - Taken Together | Lomitapide & Atorvastatin - Approx. 12 Hours Between | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 16 Participants | 32 Participants |
| Age, Continuous | 41 years STANDARD_DEVIATION 9.1 | 39 years STANDARD_DEVIATION 9.5 | 40 years STANDARD_DEVIATION 9.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 12 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 4 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 2 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 13 Participants | 21 Participants |
| Region of Enrollment United States | 16 participants | 16 participants | 32 participants |
| Sex: Female, Male Female | 8 Participants | 8 Participants | 16 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 12 / 16 | 5 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 |
Outcome results
Primary
AUC0-∞
Area under the concentration-time curve from zero to infinity of lomitapide and its 2 primary metabolites (M1 & M3), following administration of lomitapide alone and coadministered with atorvastatin simultaneously (Arm 1)
Time frame: Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK Population consisted of all subjects who received at least one dose of study drug and had evaluable PK data. 2 subjects were removed from formal statistical analysis of PK of M3 (Lomitapide alone) due to missing value of AUC0-∞ for Analyte M3.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK of Lomitapide (Lomitapide Alone) | AUC0-∞ | 40.4 ng*hr/mL | Geometric Coefficient of Variation 40.8 |
| PK of Lomitapide (Coadministered Simultaneously) | AUC0-∞ | 76.7 ng*hr/mL | Geometric Coefficient of Variation 45.1 |
| PK of M1 (Lomitapide Alone) | AUC0-∞ | 79.1 ng*hr/mL | Geometric Coefficient of Variation 34.7 |
| PK of M1 (Coadministered Simultaneously) | AUC0-∞ | 78.7 ng*hr/mL | Geometric Coefficient of Variation 36.3 |
| PK of M3 (Lomitapide Alone) | AUC0-∞ | 469 ng*hr/mL | Geometric Coefficient of Variation 68.6 |
| PK of M3 (Coadministered Simultaneously) | AUC0-∞ | 487 ng*hr/mL | Geometric Coefficient of Variation 544 |
Primary
AUC0-t
Area under the concentration-time curve from zero to the last quantifiable concentration of lomitapide and its 2 primary metabolites (M1 & M3), following administration of lomitapide alone and coadministered with atorvastatin simultaneously (Arm 1)
Time frame: Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK Population consisted of all subjects who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK of Lomitapide (Lomitapide Alone) | AUC0-t | 36.4 ng*hr/mL | Geometric Coefficient of Variation 38.4 |
| PK of Lomitapide (Coadministered Simultaneously) | AUC0-t | 71.5 ng*hr/mL | Geometric Coefficient of Variation 45.3 |
| PK of M1 (Lomitapide Alone) | AUC0-t | 76.8 ng*hr/mL | Geometric Coefficient of Variation 34.4 |
| PK of M1 (Coadministered Simultaneously) | AUC0-t | 76.3 ng*hr/mL | Geometric Coefficient of Variation 36 |
| PK of M3 (Lomitapide Alone) | AUC0-t | 434 ng*hr/mL | Geometric Coefficient of Variation 65.5 |
| PK of M3 (Coadministered Simultaneously) | AUC0-t | 475 ng*hr/mL | Geometric Coefficient of Variation 55 |
Primary
Cmax
Maximum observed plasma concentration of lomitapide and its 2 primary metabolites (M1 & M3), following administration of lomitapide alone and coadministered with atorvastatin simultaneously (Arm 1)
Time frame: Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK Population consisted of all subjects who received at least one dose of study drug and have evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK of Lomitapide (Lomitapide Alone) | Cmax | 0.940 ng/mL | Geometric Coefficient of Variation 34.5 |
| PK of Lomitapide (Coadministered Simultaneously) | Cmax | 2.00 ng/mL | Geometric Coefficient of Variation 52.9 |
| PK of M1 (Lomitapide Alone) | Cmax | 2.24 ng/mL | Geometric Coefficient of Variation 22.8 |
| PK of M1 (Coadministered Simultaneously) | Cmax | 2.11 ng/mL | Geometric Coefficient of Variation 31.9 |
| PK of M3 (Lomitapide Alone) | Cmax | 32.3 ng/mL | Geometric Coefficient of Variation 40.6 |
| PK of M3 (Coadministered Simultaneously) | Cmax | 27.2 ng/mL | Geometric Coefficient of Variation 62 |
Primary
t1/2
Apparent terminal elimination half-life of lomitapide and its 2 primary metabolites (M1 & M3), following administration of lomitapide alone and coadministered with atorvastatin simultaneously (Arm 1)
Time frame: Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK Population consisted of all subjects who received at least one dose of study drug and have evaluable PK data. 2 subjects were removed from formal statistical analysis of PK of M3 (Lomitapide alone) due to missing value of AUC0-∞ for Analyte M3.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK of Lomitapide (Lomitapide Alone) | t1/2 | 50.7 hr | Geometric Coefficient of Variation 22.1 |
| PK of Lomitapide (Coadministered Simultaneously) | t1/2 | 50.4 hr | Geometric Coefficient of Variation 21.8 |
| PK of M1 (Lomitapide Alone) | t1/2 | 34.0 hr | Geometric Coefficient of Variation 17.7 |
| PK of M1 (Coadministered Simultaneously) | t1/2 | 35.2 hr | Geometric Coefficient of Variation 16.2 |
| PK of M3 (Lomitapide Alone) | t1/2 | 50.2 hr | Geometric Coefficient of Variation 25.6 |
| PK of M3 (Coadministered Simultaneously) | t1/2 | 43.2 hr | Geometric Coefficient of Variation 18.4 |
Primary
Tmax
Time to reach maximum observed plasma concentration of lomitapide and its 2 primary metabolites (M1 & M3), following administration of lomitapide alone and coadministered with atorvastatin simultaneously (Arm 1)
Time frame: Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK Population consisted of all subjects who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PK of Lomitapide (Lomitapide Alone) | Tmax | 6.00 hr |
| PK of Lomitapide (Coadministered Simultaneously) | Tmax | 10.0 hr |
| PK of M1 (Lomitapide Alone) | Tmax | 6.02 hr |
| PK of M1 (Coadministered Simultaneously) | Tmax | 10.0 hr |
| PK of M3 (Lomitapide Alone) | Tmax | 4.00 hr |
| PK of M3 (Coadministered Simultaneously) | Tmax | 6.00 hr |
Secondary
AUC0-∞
Area under the concentration-time curve from zero to infinity of lomitapide and its 2 primary metabolites (M1 & M3) following administration of lomitapide alone and coadministered with atorvastatin 12 hours apart (Arm 2)
Time frame: Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK Population consisted of all subjects who received at least one dose of study drug and have evaluable PK data. 3 subjects were removed from formal statistical analysis due to BLQ values on Day 1, missing value of AUC0-∞ on Day 1, and missing value of AUC0-∞ on Day 15.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK of Lomitapide (Lomitapide Alone) | AUC0-∞ | 42.8 ng*hr/mL | Geometric Coefficient of Variation 39.6 |
| PK of Lomitapide (Coadministered Simultaneously) | AUC0-∞ | 55.8 ng*hr/mL | Geometric Coefficient of Variation 25.2 |
| PK of M1 (Lomitapide Alone) | AUC0-∞ | 70.0 ng*hr/mL | Geometric Coefficient of Variation 32.8 |
| PK of M1 (Coadministered Simultaneously) | AUC0-∞ | 79.2 ng*hr/mL | Geometric Coefficient of Variation 27.8 |
| PK of M3 (Lomitapide Alone) | AUC0-∞ | 406 ng*hr/mL | Geometric Coefficient of Variation 30.8 |
| PK of M3 (Coadministered Simultaneously) | AUC0-∞ | 553 ng*hr/mL | Geometric Coefficient of Variation 32.4 |
Secondary
AUC0-t
Area under the concentration-time curve from zero to the last quantifiable concentration of lomitapide and its 2 primary metabolites (M1 & M3) following administration of lomitapide alone and coadministered with atorvastatin 12 hours apart (Arm 2)
Time frame: Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK Population consisted of all subjects who received at least one dose of study drug and have evaluable PK data. 1 subject was removed from formal statistical analysis due to all BLQ values on Day 1 for lomitapide, M1 and M3.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK of Lomitapide (Lomitapide Alone) | AUC0-t | 38.8 ng*hr/mL | Geometric Coefficient of Variation 40.8 |
| PK of Lomitapide (Coadministered Simultaneously) | AUC0-t | 50.5 ng*hr/mL | Geometric Coefficient of Variation 26 |
| PK of M1 (Lomitapide Alone) | AUC0-t | 68.3 ng*hr/mL | Geometric Coefficient of Variation 33 |
| PK of M1 (Coadministered Simultaneously) | AUC0-t | 77.6 ng*hr/mL | Geometric Coefficient of Variation 27.9 |
| PK of M3 (Lomitapide Alone) | AUC0-t | 410 ng*hr/mL | Geometric Coefficient of Variation 32.6 |
| PK of M3 (Coadministered Simultaneously) | AUC0-t | 542 ng*hr/mL | Geometric Coefficient of Variation 31.2 |
Secondary
Cmax
Maximum observed plasma concentration of lomitapide and its 2 primary metabolites (M1 & M3) following administration of lomitapide alone and coadministered with atorvastatin 12 hours apart (Arm 2)
Time frame: Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK Population consisted of all subjects who received at least one dose of study drug and have evaluable PK data. 1 subject was removed from formal statistical analysis due to all BLQ values on Day 1 for lomitapide, M1 and M3.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK of Lomitapide (Lomitapide Alone) | Cmax | 1.09 ng/mL | Geometric Coefficient of Variation 49.8 |
| PK of Lomitapide (Coadministered Simultaneously) | Cmax | 1.39 ng/mL | Geometric Coefficient of Variation 40 |
| PK of M1 (Lomitapide Alone) | Cmax | 2.38 ng/mL | Geometric Coefficient of Variation 25.5 |
| PK of M1 (Coadministered Simultaneously) | Cmax | 2.66 ng/mL | Geometric Coefficient of Variation 25.4 |
| PK of M3 (Lomitapide Alone) | Cmax | 28.5 ng/mL | Geometric Coefficient of Variation 29.9 |
| PK of M3 (Coadministered Simultaneously) | Cmax | 35.9 ng/mL | Geometric Coefficient of Variation 27.3 |
Secondary
t1/2
Apparent terminal elimination half-life of lomitapide and its 2 primary metabolites (M1 & M3) following administration of lomitapide alone and coadministered with atorvastatin 12 hours apart (Arm 2)
Time frame: Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK Population consisted of all subjects who received at least one dose of study drug and have evaluable PK data. 3 subjects were removed from formal statistical analysis due to BLQ values on Day 1, missing value of AUC0-∞ on Day 1, and missing value of AUC0-∞ on Day 15.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| PK of Lomitapide (Lomitapide Alone) | t1/2 | 52.0 hr | Geometric Coefficient of Variation 19.5 |
| PK of Lomitapide (Coadministered Simultaneously) | t1/2 | 54.7 hr | Geometric Coefficient of Variation 28.5 |
| PK of M1 (Lomitapide Alone) | t1/2 | 31.2 hr | Geometric Coefficient of Variation 24 |
| PK of M1 (Coadministered Simultaneously) | t1/2 | 32.3 hr | Geometric Coefficient of Variation 18.2 |
| PK of M3 (Lomitapide Alone) | t1/2 | 48.0 hr | Geometric Coefficient of Variation 33.4 |
| PK of M3 (Coadministered Simultaneously) | t1/2 | 49.7 hr | Geometric Coefficient of Variation 21.9 |
Secondary
Tmax
Time to reach maximum observed plasma concentration of lomitapide and its 2 primary metabolites (M1 & M3) following administration of lomitapide alone and coadministered with atorvastatin 12 hours apart (Arm 2)
Time frame: Predose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 144, and 168 hours after dosing
Population: The PK Population consisted of all subjects who received at least one dose of study drug and have evaluable PK data. 1 subject was removed from formal statistical analysis due to all BLQ values on Day 1 for lomitapide, M1 and M3.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PK of Lomitapide (Lomitapide Alone) | Tmax | 8.02 hr |
| PK of Lomitapide (Coadministered Simultaneously) | Tmax | 8.00 hr |
| PK of M1 (Lomitapide Alone) | Tmax | 8.00 hr |
| PK of M1 (Coadministered Simultaneously) | Tmax | 8.00 hr |
| PK of M3 (Lomitapide Alone) | Tmax | 6.00 hr |
| PK of M3 (Coadministered Simultaneously) | Tmax | 5.00 hr |