Essential Thrombocythaemia Myelofibrosis, Post-Polycythaemia Vera, Primary Myelofibrosis (PMF)
Conditions
Keywords
Primary Myelofibrosis (PMF), Post-Polycythaemia Vera/Essential Thrombocythaemia Myelofibrosis (Post-PV/ET MF), Myeloproliferative diseases, Phase I, Phase II, Bone marrow
Brief summary
This study is being conducted to test study drug AZD1480 to see how it may work to treat myeloproliferative diseases. The main purpose of this study is to determine the safety and tolerability of AZD1480. This is the first time the drug has been given to humans and is classed as a first time in man study. Its main purpose is to establish a safe dosage of the drug and provide additional information on any potential side effects this drug may cause. The study will also assess the blood levels and action of AZD1480 in the body over a period of time and will indicate whether the drug has a therapeutic effect on myeloproliferative diseases.
Interventions
DRUGAZD1480
Oral capsule 2.5 mg, 10 mg and 40 mg
Sponsors
University of Texas
New York City Hoffman Center
Gustave Roussy, Cancer Campus, Grand Paris
AstraZeneca
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
25 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Patients with myelofibrosis requiring therapy * Evidence of post-menopausal status or sterile * ECOG Performance Status \</=2
Exclusion criteria
* Prior therapy with any JAK2 medications * Significant lung disorder or lung disease * Previous radiation therapy to chest wall or chest infection requiring antibiotic treatment within 28 days before study screening * Eye disease of the cornea * Patients requiring oxygen supplementation * Ejection fraction \<45% (ECHO/MUGA) or significant pulmonary hypertension \>40 mm Hg (by Echo/Doppler) * Forced Expiratory Volume (FEV1)/Forced Vital Capacity (FVC) \<70% predicted or \>130% predicted * Diffusing capacity of the Lung for Carbon Monoxide (DLCO) corrected for hemoglobin \<60% predicted, oxygen saturation \<88% at rest or after a 6-minute flat walk, without supplemental oxygen * Chest infection requiring antibiotics within 7 days of the first dose of Investigational product.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Parameters Following Multiple Dosing: Cmin,ss | On Days 1 and 28 at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose and at 0, 2, 4 hours post-dose on Days 4 and 10. | Multiple dose Cmin,ss (ug/L) |
| Pharmacokinetic Parameters Following Single Dosing: Cmax | 0 to 24 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post dose) | Single dose Cmax (ug/L) |
| Pharmacokinetic Parameters Following Single Dosing: AUC0-12 | 0 to 12 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post dose) | Single dose AUC0-12 (ug\*h/L) |
| Pharmacokinetic Parameters Following Single Dosing: AUC0-24 | 0 to 24 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post dose) | Single dose AUC0-24 (ug\*h/L) |
| Pharmacokinetic Parameters Following Single Dosing:AUC0-inf | 0 to 24 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post dose) | Single dose AUC(0 to infinity) (ug\*h/L) |
| Pharmacokinetic Parameters Following Multiple Dosing: Cmax,ss | On Days 1 and 28 at 0, 0,5, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post dose, and at 0, 2, 4 hours post dose on Days 4 and 10 | Multiple dose Cmax,ss (ug/L) |
| Pharmacokinetic Parameters Following Single Dosing: Vz/F | 0 to 24 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post dose) | Single dose Vz/F (L) |
| Pharmacokinetic Parameters Following Single Dosing: CL/F | 0 to 24 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post dose) | Single dose CL/F (L/h) |
| Pharmacokinetic Parameters Following Multiple Dosing: CLss/F | On Days 1 and 28 at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 hours post dose and at 0, 2, 4 hours post-dose | Multiple dose CLss/F (L/h) |
| Pharamcokinetic Parameters Following Single Dosing: Tmax | 0 to 24 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post dose) | Single dose Tmax (h) |
| Pharamcokinetic Parameters Following Multiple Dosing: Tmax,ss | On Days 1 and 28 at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post dose and at 0, 2, 4 hours post-dose on Days 4 and 10 | Multiple dose Tmax,ss (h) |
| Inhibition of PSTAT3 (Count) | 2hrs and 4 hrs post dose | PSTAT3 inhinition |
Countries
France, United States
Participant flow
Recruitment details
Commenced 19MAY2009. All subjects recruited to Part A only (based on emerging data). 65 patients were enrolled of which 35 recieved at least 1 dose of AZD1480.
Pre-assignment details
Patients ≥25 years of age with primary myelofibrosis (MF) and post-polycythaemia vera/essential thrombocythaemia MF who had relapsed, were intolerant of, or were refractory to MF-directed therapy were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| 2.5 mg QD AZD1480 may be administered orally in capsules | 6 |
| 5.0 mg QD AZD1480 may be administered orally in capsules | 3 |
| 10 mg QD AZD1480 may be administered orally in capsules | 3 |
| 70 mg QD AZD1480 may be administered orally in capsules | 1 |
| 15 mg BID AZD1480 may be administered orally in capsules | 4 |
| 30 mg QD AZD1480 may be administered orally in capsules | 3 |
| 50 mg QD AZD1480 may be administered orally in capsules | 6 |
| 10 mg BID AZD1480 may be administered orally in capsules | 6 |
| 20 mg QD AZD1480 may be administered orally in capsules | 3 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 1 | 1 | 0 | 0 | 2 | 1 | 1 |
| Overall Study | Lack of Efficacy | 2 | 3 | 1 | 2 | 1 | 0 | 2 | 2 | 2 |
| Overall Study | (not specified) | 2 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 3 | 1 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | 2.5 mg QD | 5.0 mg QD | 10 mg QD | 70 mg QD | 15 mg BID | 30 mg QD | 50 mg QD | 10 mg BID | 20 mg QD | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 57.5 years STANDARD_DEVIATION 7.7 | 66.3 years STANDARD_DEVIATION 9.6 | 76.7 years STANDARD_DEVIATION 10.5 | 56.0 years STANDARD_DEVIATION 0 | 66.5 years STANDARD_DEVIATION 10.3 | 49.3 years STANDARD_DEVIATION 4.2 | 69.3 years STANDARD_DEVIATION 3.8 | 65.3 years STANDARD_DEVIATION 11.3 | 75.7 years STANDARD_DEVIATION 3.8 | 65.1 years STANDARD_DEVIATION 10.6 |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 5 Participants | 2 Participants | 2 Participants | 14 Participants |
| Sex: Female, Male Male | 5 Participants | 2 Participants | 2 Participants | 0 Participants | 4 Participants | 2 Participants | 1 Participants | 4 Participants | 1 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 3 / 3 | 3 / 3 | 1 / 1 | 4 / 4 | 3 / 3 | 3 / 3 | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 2 / 6 | 2 / 3 | 0 / 3 | 0 / 1 | 1 / 4 | 3 / 3 | 0 / 3 | 4 / 6 | 3 / 6 |
Outcome results
Primary
Inhibition of PSTAT3 (Count)
PSTAT3 inhinition
Time frame: 2hrs and 4 hrs post dose
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 2.5 mg QD | Inhibition of PSTAT3 (Count) | 2 Hours post dose | 0 # patients with 50% reduction in PSTAT3 |
| 2.5 mg QD | Inhibition of PSTAT3 (Count) | 4 Hours post dose | 0 # patients with 50% reduction in PSTAT3 |
| 5.0 mg QD | Inhibition of PSTAT3 (Count) | 4 Hours post dose | 0 # patients with 50% reduction in PSTAT3 |
| 5.0 mg QD | Inhibition of PSTAT3 (Count) | 2 Hours post dose | 0 # patients with 50% reduction in PSTAT3 |
| 10 mg QD | Inhibition of PSTAT3 (Count) | 2 Hours post dose | 0 # patients with 50% reduction in PSTAT3 |
| 10 mg QD | Inhibition of PSTAT3 (Count) | 4 Hours post dose | 0 # patients with 50% reduction in PSTAT3 |
| 30 mg QD | Inhibition of PSTAT3 (Count) | 4 Hours post dose | 0 # patients with 50% reduction in PSTAT3 |
| 30 mg QD | Inhibition of PSTAT3 (Count) | 2 Hours post dose | 1 # patients with 50% reduction in PSTAT3 |
| 70 mg QD | Inhibition of PSTAT3 (Count) | 4 Hours post dose | 0 # patients with 50% reduction in PSTAT3 |
| 70 mg QD | Inhibition of PSTAT3 (Count) | 2 Hours post dose | 0 # patients with 50% reduction in PSTAT3 |
| 10 mg BID | Inhibition of PSTAT3 (Count) | 2 Hours post dose | 0 # patients with 50% reduction in PSTAT3 |
| 10 mg BID | Inhibition of PSTAT3 (Count) | 4 Hours post dose | 1 # patients with 50% reduction in PSTAT3 |
| 15 mg BID | Inhibition of PSTAT3 (Count) | 2 Hours post dose | 0 # patients with 50% reduction in PSTAT3 |
| 15 mg BID | Inhibition of PSTAT3 (Count) | 4 Hours post dose | 0 # patients with 50% reduction in PSTAT3 |
| 50 mg QD | Inhibition of PSTAT3 (Count) | 2 Hours post dose | 3 # patients with 50% reduction in PSTAT3 |
| 50 mg QD | Inhibition of PSTAT3 (Count) | 4 Hours post dose | 0 # patients with 50% reduction in PSTAT3 |
| 20 mg QD | Inhibition of PSTAT3 (Count) | 2 Hours post dose | 0 # patients with 50% reduction in PSTAT3 |
| 20 mg QD | Inhibition of PSTAT3 (Count) | 4 Hours post dose | 0 # patients with 50% reduction in PSTAT3 |
Primary
Pharamcokinetic Parameters Following Multiple Dosing: Tmax,ss
Multiple dose Tmax,ss (h)
Time frame: On Days 1 and 28 at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post dose and at 0, 2, 4 hours post-dose on Days 4 and 10
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 2.5 mg QD | Pharamcokinetic Parameters Following Multiple Dosing: Tmax,ss | 0.5 h |
| 5.0 mg QD | Pharamcokinetic Parameters Following Multiple Dosing: Tmax,ss | 0.78 h |
| 10 mg QD | Pharamcokinetic Parameters Following Multiple Dosing: Tmax,ss | 0.77 h |
| 30 mg QD | Pharamcokinetic Parameters Following Multiple Dosing: Tmax,ss | 0.75 h |
| 70 mg QD | Pharamcokinetic Parameters Following Multiple Dosing: Tmax,ss | 1.5 h |
| 10 mg BID | Pharamcokinetic Parameters Following Multiple Dosing: Tmax,ss | 1 h |
| 15 mg BID | Pharamcokinetic Parameters Following Multiple Dosing: Tmax,ss | 0.875 h |
| 50 mg QD | Pharamcokinetic Parameters Following Multiple Dosing: Tmax,ss | 0.78 h |
| 20 mg QD | Pharamcokinetic Parameters Following Multiple Dosing: Tmax,ss | 1 h |
Primary
Pharamcokinetic Parameters Following Single Dosing: Tmax
Single dose Tmax (h)
Time frame: 0 to 24 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post dose)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 2.5 mg QD | Pharamcokinetic Parameters Following Single Dosing: Tmax | 0.625 h |
| 5.0 mg QD | Pharamcokinetic Parameters Following Single Dosing: Tmax | 0.75 h |
| 10 mg QD | Pharamcokinetic Parameters Following Single Dosing: Tmax | 0.75 h |
| 30 mg QD | Pharamcokinetic Parameters Following Single Dosing: Tmax | 1 h |
| 70 mg QD | Pharamcokinetic Parameters Following Single Dosing: Tmax | 0.75 h |
| 10 mg BID | Pharamcokinetic Parameters Following Single Dosing: Tmax | 0.625 h |
| 15 mg BID | Pharamcokinetic Parameters Following Single Dosing: Tmax | 0.875 h |
| 50 mg QD | Pharamcokinetic Parameters Following Single Dosing: Tmax | 0.89 h |
| 20 mg QD | Pharamcokinetic Parameters Following Single Dosing: Tmax | 0.75 h |
Primary
Pharmacokinetic Parameters Following Multiple Dosing: CLss/F
Multiple dose CLss/F (L/h)
Time frame: On Days 1 and 28 at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 hours post dose and at 0, 2, 4 hours post-dose
Population: Pharmacokinetic.~Note - no GeoCV(%) was captured in the TFL. Hence the geometric mean was still presented as applicable but with the SD (since only available).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 2.5 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: CLss/F | 37.8 L/h | Standard Deviation 6 |
| 5.0 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: CLss/F | 15.8 L/h | Standard Deviation 4.4 |
| 10 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: CLss/F | 30.1 L/h | Standard Deviation 21.7 |
| 30 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: CLss/F | 17 L/h | Standard Deviation 5.26 |
| 70 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: CLss/F | 9.57 L/h | Standard Deviation 0 |
| 10 mg BID | Pharmacokinetic Parameters Following Multiple Dosing: CLss/F | 20 L/h | Standard Deviation 6.91 |
| 15 mg BID | Pharmacokinetic Parameters Following Multiple Dosing: CLss/F | 20.4 L/h | Standard Deviation 13.8 |
| 50 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: CLss/F | 16 L/h | Standard Deviation 8.94 |
| 20 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: CLss/F | 20.8 L/h | Standard Deviation 21 |
Primary
Pharmacokinetic Parameters Following Multiple Dosing: Cmax,ss
Multiple dose Cmax,ss (ug/L)
Time frame: On Days 1 and 28 at 0, 0,5, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post dose, and at 0, 2, 4 hours post dose on Days 4 and 10
Population: Pharmacokinetic.~Note - no GeoCV(%) was captured in the TFL. Hence the geometric mean was still presented as applicable but with the SD (since only available).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 2.5 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: Cmax,ss | 51.3 ug/L | Standard Deviation 18 |
| 5.0 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: Cmax,ss | 134 ug/L | Standard Deviation 36.3 |
| 10 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: Cmax,ss | 176 ug/L | Standard Deviation 179 |
| 30 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: Cmax,ss | 658 ug/L | Standard Deviation 265 |
| 70 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: Cmax,ss | 1500 ug/L | Standard Deviation 0 |
| 10 mg BID | Pharmacokinetic Parameters Following Multiple Dosing: Cmax,ss | 218 ug/L | Standard Deviation 72.3 |
| 15 mg BID | Pharmacokinetic Parameters Following Multiple Dosing: Cmax,ss | 334 ug/L | Standard Deviation 68.2 |
| 50 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: Cmax,ss | 924 ug/L | Standard Deviation 461 |
| 20 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: Cmax,ss | 241 ug/L | Standard Deviation 346 |
Primary
Pharmacokinetic Parameters Following Multiple Dosing: Cmin,ss
Multiple dose Cmin,ss (ug/L)
Time frame: On Days 1 and 28 at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose and at 0, 2, 4 hours post-dose on Days 4 and 10.
Population: Pharmacokinetic.~Note - no GeoCV(%) was captured in the TFL. Hence the geometric mean was still presented as applicable but with the SD (since only available).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 2.5 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: Cmin,ss | 69.2 ug/L | Standard Deviation 27.5 |
| 5.0 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: Cmin,ss | 295 ug/L | Standard Deviation 68.2 |
| 10 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: Cmin,ss | 278 ug/L | Standard Deviation 257 |
| 30 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: Cmin,ss | 1860 ug/L | Standard Deviation 546 |
| 70 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: Cmin,ss | 5800 ug/L | Standard Deviation 0 |
| 10 mg BID | Pharmacokinetic Parameters Following Multiple Dosing: Cmin,ss | 425 ug/L | Standard Deviation 190 |
| 15 mg BID | Pharmacokinetic Parameters Following Multiple Dosing: Cmin,ss | 497 ug/L | Standard Deviation 191 |
| 50 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: Cmin,ss | 3090 ug/L | Standard Deviation 2060 |
| 20 mg QD | Pharmacokinetic Parameters Following Multiple Dosing: Cmin,ss | 472 ug/L | Standard Deviation 257 |
Primary
Pharmacokinetic Parameters Following Single Dosing: AUC0-12
Single dose AUC0-12 (ug\*h/L)
Time frame: 0 to 12 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post dose)
Population: Pharmacokinetic.~Note - no GeoCV(%) was captured in the TFL. Hence the geometric mean was still presented as applicable but with the SD (since only available).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 2.5 mg QD | Pharmacokinetic Parameters Following Single Dosing: AUC0-12 | 69.2 ug*h/L | Standard Deviation 27.5 |
| 5.0 mg QD | Pharmacokinetic Parameters Following Single Dosing: AUC0-12 | 295 ug*h/L | Standard Deviation 68.2 |
| 10 mg QD | Pharmacokinetic Parameters Following Single Dosing: AUC0-12 | 278 ug*h/L | Standard Deviation 257 |
| 30 mg QD | Pharmacokinetic Parameters Following Single Dosing: AUC0-12 | 1860 ug*h/L | Standard Deviation 546 |
| 70 mg QD | Pharmacokinetic Parameters Following Single Dosing: AUC0-12 | 5800 ug*h/L | Standard Deviation 0 |
| 10 mg BID | Pharmacokinetic Parameters Following Single Dosing: AUC0-12 | 425 ug*h/L | Standard Deviation 190 |
| 15 mg BID | Pharmacokinetic Parameters Following Single Dosing: AUC0-12 | 497 ug*h/L | Standard Deviation 191 |
| 50 mg QD | Pharmacokinetic Parameters Following Single Dosing: AUC0-12 | 3090 ug*h/L | Standard Deviation 2060 |
| 20 mg QD | Pharmacokinetic Parameters Following Single Dosing: AUC0-12 | 472 ug*h/L | Standard Deviation 257 |
Primary
Pharmacokinetic Parameters Following Single Dosing: AUC0-24
Single dose AUC0-24 (ug\*h/L)
Time frame: 0 to 24 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post dose)
Population: Pharmacokinetic.~Note - no GeoCV(%) was captured in the TFL. Hence the geometric mean was still presented as applicable but with the SD (since only available).~From the BID schedule we can not derive the single dosing AUC0\_24 and hence this is not presented/calculated.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 2.5 mg QD | Pharmacokinetic Parameters Following Single Dosing: AUC0-24 | 70.2 ug*h/L | Standard Deviation 28.7 |
| 5.0 mg QD | Pharmacokinetic Parameters Following Single Dosing: AUC0-24 | 308 ug*h/L | Standard Deviation 76 |
| 10 mg QD | Pharmacokinetic Parameters Following Single Dosing: AUC0-24 | 285 ug*h/L | Standard Deviation 252 |
| 30 mg QD | Pharmacokinetic Parameters Following Single Dosing: AUC0-24 | 2000 ug*h/L | Standard Deviation 624 |
| 70 mg QD | Pharmacokinetic Parameters Following Single Dosing: AUC0-24 | 6260 ug*h/L | Standard Deviation 0 |
| 50 mg QD | Pharmacokinetic Parameters Following Single Dosing: AUC0-24 | 3540 ug*h/L | Standard Deviation 2570 |
| 20 mg QD | Pharmacokinetic Parameters Following Single Dosing: AUC0-24 | 508 ug*h/L | Standard Deviation 280 |
Primary
Pharmacokinetic Parameters Following Single Dosing:AUC0-inf
Single dose AUC(0 to infinity) (ug\*h/L)
Time frame: 0 to 24 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post dose)
Population: Pharmacokinetic.~Note - no GeoCV(%) was captured in the TFL. Hence the geometric mean was still presented as applicable but with the SD (since only available).~From the BID (twice a day dosing schedules) we can not derive the PK parameter AUC0\_inf following single dosing. With that these do not contribute.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 2.5 mg QD | Pharmacokinetic Parameters Following Single Dosing:AUC0-inf | 83.5 ug*h/L | Standard Deviation 36.6 |
| 5.0 mg QD | Pharmacokinetic Parameters Following Single Dosing:AUC0-inf | 312 ug*h/L | Standard Deviation 79.5 |
| 10 mg QD | Pharmacokinetic Parameters Following Single Dosing:AUC0-inf | 378 ug*h/L | Standard Deviation 290 |
| 30 mg QD | Pharmacokinetic Parameters Following Single Dosing:AUC0-inf | 2040 ug*h/L | Standard Deviation 657 |
| 70 mg QD | Pharmacokinetic Parameters Following Single Dosing:AUC0-inf | 6300 ug*h/L | Standard Deviation 0 |
| 50 mg QD | Pharmacokinetic Parameters Following Single Dosing:AUC0-inf | 3650 ug*h/L | Standard Deviation 2980 |
| 20 mg QD | Pharmacokinetic Parameters Following Single Dosing:AUC0-inf | 517 ug*h/L | Standard Deviation 294 |
Primary
Pharmacokinetic Parameters Following Single Dosing: CL/F
Single dose CL/F (L/h)
Time frame: 0 to 24 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post dose)
Population: Pharmacokinetic.~Note - no GeoCV(%) was captured in the TFL. Hence the geometric mean was still presented as applicable but with the SD (since only available).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 2.5 mg QD | Pharmacokinetic Parameters Following Single Dosing: CL/F | 35.2 L/h | Standard Deviation 13.9 |
| 5.0 mg QD | Pharmacokinetic Parameters Following Single Dosing: CL/F | 16 L/h | Standard Deviation 4.25 |
| 10 mg QD | Pharmacokinetic Parameters Following Single Dosing: CL/F | 34.8 L/h | Standard Deviation 22.5 |
| 30 mg QD | Pharmacokinetic Parameters Following Single Dosing: CL/F | 14.7 L/h | Standard Deviation 5.52 |
| 70 mg QD | Pharmacokinetic Parameters Following Single Dosing: CL/F | 11.1 L/h | Standard Deviation 0 |
| 10 mg BID | Pharmacokinetic Parameters Following Single Dosing: CL/F | 22.6 L/h | Standard Deviation 9.05 |
| 15 mg BID | Pharmacokinetic Parameters Following Single Dosing: CL/F | 29.7 L/h | Standard Deviation 13 |
| 50 mg QD | Pharmacokinetic Parameters Following Single Dosing: CL/F | 13.8 L/h | Standard Deviation 8.5 |
| 20 mg QD | Pharmacokinetic Parameters Following Single Dosing: CL/F | 38.7 L/h | Standard Deviation 16.7 |
Primary
Pharmacokinetic Parameters Following Single Dosing: Cmax
Single dose Cmax (ug/L)
Time frame: 0 to 24 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post dose)
Population: Pharmacokinetic.~Note - no GeoCV(%) was captured in the TFL. Hence the geometric mean was still presented as applicable but with the SD (since only available).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 2.5 mg QD | Pharmacokinetic Parameters Following Single Dosing: Cmax | 69.9 ug/L | Standard Deviation 32.7 |
| 5.0 mg QD | Pharmacokinetic Parameters Following Single Dosing: Cmax | 133 ug/L | Standard Deviation 54.7 |
| 10 mg QD | Pharmacokinetic Parameters Following Single Dosing: Cmax | 157 ug/L | Standard Deviation 145 |
| 30 mg QD | Pharmacokinetic Parameters Following Single Dosing: Cmax | 739 ug/L | Standard Deviation 307 |
| 70 mg QD | Pharmacokinetic Parameters Following Single Dosing: Cmax | 2600 ug/L | Standard Deviation 0 |
| 10 mg BID | Pharmacokinetic Parameters Following Single Dosing: Cmax | 273 ug/L | Standard Deviation 62.2 |
| 15 mg BID | Pharmacokinetic Parameters Following Single Dosing: Cmax | 324 ug/L | Standard Deviation 79.5 |
| 50 mg QD | Pharmacokinetic Parameters Following Single Dosing: Cmax | 1320 ug/L | Standard Deviation 379 |
| 20 mg QD | Pharmacokinetic Parameters Following Single Dosing: Cmax | 268 ug/L | Standard Deviation 227 |
Primary
Pharmacokinetic Parameters Following Single Dosing: Vz/F
Single dose Vz/F (L)
Time frame: 0 to 24 hour sampling (Day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post dose)
Population: Pharmacokinetic.~Note - no GeoCV(%) was captured in the TFL. Hence the geometric mean was still presented as applicable but with the SD (since only available).~Due to the nature of the dosing schedule this PK parameter was not reported for the BID (twice daily dosing) groups.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 2.5 mg QD | Pharmacokinetic Parameters Following Single Dosing: Vz/F | 222 L | Standard Deviation 125 |
| 5.0 mg QD | Pharmacokinetic Parameters Following Single Dosing: Vz/F | 108 L | Standard Deviation 28.1 |
| 10 mg QD | Pharmacokinetic Parameters Following Single Dosing: Vz/F | 138 L | Standard Deviation 161 |
| 30 mg QD | Pharmacokinetic Parameters Following Single Dosing: Vz/F | 97 L | Standard Deviation 15 |
| 70 mg QD | Pharmacokinetic Parameters Following Single Dosing: Vz/F | 57.9 L | Standard Deviation 0 |
| 50 mg QD | Pharmacokinetic Parameters Following Single Dosing: Vz/F | 105 L | Standard Deviation 82.2 |
| 20 mg QD | Pharmacokinetic Parameters Following Single Dosing: Vz/F | 284 L | Standard Deviation 92.3 |