Neurofibromatosis Type 1
Conditions
Brief summary
This study is designed to define a dosing regimen and assess the pharmacokinetics(PK) and safety of the granule formulation; the study will also include descriptive analyses of exploratory efficacy endpoints. The study will inform the benefit risk profile of the granule formulation in children aged ≥ 1 to \< 7 years with NF1 related symptomatic, inoperable PN.
Detailed description
This is a Phase I/II, single arm, open-label study in children aged ≥ 1 to \< 7 years at study entry (date of ICF signature) with a clinical diagnosis of NF1 related symptomatic, inoperable PN. The study is designed to evaluate the PK, safety and tolerability of selumetinib given as a granule formulation. Participants will receive selumetinib for 25 cycles (or until they meet discontinuation criteria). Enrolment into the initial dose-finding phase will be stratified by age group: * Cohort 1: participants aged between ≥ 4 and \< 7 years * Cohort 2: participants aged between ≥ 1 to \< 4 years In addition to the Global Cohorts, 6 Japanese participants in Japan aged between ≥ 1 to \< 7 years with NF1 related symptomatic, inoperable PN will be enrolled into the Japan Cohort. After completion of at least one cycle (28 days) of dosing in 3 evaluable participants in Cohort 1, Safety Review Committee(SRC) will review the emerging safety and PK data. Providing the single dose PK exposure is within the acceptable range and there are no safety concerns as determined by SRC then dosing in Cohort 2 will be initiated and additional participants will be dosed in Cohort 1. If the PK exposure is not within the acceptable range, the dose schema may be adjusted to ensure that selumetinib exposure is within the range observed in the SPRINT study; PK will be assessed against acceptance criteria in an additional 3 evaluable cohort 1 participants who received the adjusted dose. Cohort 2 will be initiated once the selumetinib granule formulation dose schema is identified for Cohort 1. The physiologically-based PK model will be updated, if required, based on emerging PK data. Additional SRC reviews will be held for each of the cohorts following at least one cycle of dosing in approximately 6 evaluable participants and again in approximately 10 evaluable participants. The SRC will evaluate the PK, safety and tolerability of the granule formulation for that dose schema. The Japan Cohort will not participate in the dose-finding phase. Participants who are aged ≥ 5 years at the end of 25 cycles of selumetinib will be considered to have completed the study for data analysis purposes. Participants who terminate treatment prior to Cycle 25 will be followed up to collect MRIs performed as standard of care and details of NF1-PN treatment information until the time when they would have completed 25 cycles of treatment, or they commence an alternative systemic NF1-PN treatment, whichever is the earliest. Any participant who is aged \< 5 years after 25 cycles of selumetinib (or when they terminate treatment with selumetinib) will enter a safety follow-up phase. Participation in the safety follow-up will continue until they reach the age of 5 years or commence an alternative systemic NF1-PN treatment, whichever is the earlier. Participants can continue to receive selumetinib (capsule or sprinkle capsule) during the safety follow-up as long as they are considered to be receiving benefit in the opinion of their Investigator.
Interventions
DRUGSelumetinib granule formulation
Selumetinib granule formulation will be administered using BSA-based dosing. The granule formulation dose schema to be used in the study will be established in the dose finding phase. At enrolment participants must have a BSA within the range 0.40 to 1.09 m2; once participants attain a BSA between 1.10 and 1.29 m2 they will be encouraged to transition to the capsule formulation, if feasible, although all participants must remain on the granule formulation until after they have completed their third cycle of treatment.
DRUGSelumetinib capsule formulation
Selumetinib capsule formulation will be administered using BSA-based dosing. Once participants attain a BSA between 1.10 and 1.29 m2 they will be encouraged to transition to the capsule formulation, if feasible, although all participants must remain on the granule formulation until after they have completed their third cycle of treatment.
Sponsors
AstraZeneca
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 6 Years
Healthy volunteers
No
Inclusion criteria
1. Male and female participants aged ≥ 1 to \< 7 years of age at the time their legally authorised representative (parent or guardian) signs the informed consent. 2. All study participants must be diagnosed with NF1 with symptomatic inoperable PN as defined in protocol. 3. Participants must have at least one measurable PN, defined as a PN of at least 3 cm measured in one dimension, which can be seen on at least 3 imaging slices and have a reasonably well-defined contour. Participants who have undergone surgery for resection of a PN are eligible provided the PN was incompletely resected and is measurable. The target PN will be defined as the clinically most relevant PN, which is symptomatic, inoperable and measurable by volumetric MRI analysis. 4. Performance status: Participants must have a Lansky performance of ≥ 70 except in participants who are wheelchair bound or have limited mobility secondary to a need for mechanical breathing support (such as an airway PN requiring tracheostomy or continuous positive airway pressure) who must have a Lansky performance of ≥ 40. 5. Participants must have a BSA ≥ 0.4 and ≤ 1.09 m2 at study entry (date of ICF signature). 6. Mandatory provision of consent for the study signed and dated by a participant's legally authorised representative (parent or guardian) along with the paediatric assent form, if applicable.
Exclusion criteria
1. Participants with confirmed or suspected malignant glioma or MPNST. Participants with low grade glioma (including optic glioma) not requiring systemic therapy are permitted. 2. History of malignancy except for malignancy treatment with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk of recurrence. 3. Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of selumetinib. 4. A life-threatening illness, medical condition, organ system dysfunction or laboratory finding which, in the Investigator's opinion, could compromise the participant's safety, interfere with the absorption or metabolism of selumetinib, or put the study outcomes at undue risk. 5. Participants with clinically significant cardiovascular disease as defined in the protocol. 6. Liver function tests: Bilirubin \> 1.5 × the ULN for age with the exception of those with Gilbert syndrome (≥ 3 × ULN) or AST/ALT \> 2 × ULN. 7. Renal Function: Creatinine clearance or radioisotope glomerular filtration rate \< 60 mL/min/1.73 m2 or Serum creatinine \> 0.8 mg/dL (for participants aged ≥ 1 to \< 4 years) or \> 1.0 mg/dL (for participants aged ≥ 4 years). 8. Participants with ophthalmological findings/condition as listed in the protocol. 9. Have any unresolved chronic toxicity with CTCAE Grade ≥ 2 which are associated with previous therapy for NF1-PN (except hair changes such as alopecia or hair lightening) 10. Participants who have previously been treated with a MEKi (including selumetinib) and have had disease progression, or due to toxicity have either discontinued treatment and/or required a dose reduction. 11. Have inadequate haematological function defined as: An absolute neutrophil count \< 1500/μL or Haemoglobin \< 9g/dL or Platelets \<100,000/μL or Have had a transfusion (of red cells or other blood derived products) within the 28 days prior to study entry (date of ICF signature). 12. Have received or are receiving an IMP or other systemic NF1-PN target treatment (including MEKi) within 4 weeks prior to the first dose of study intervention, or within a period during which the IMP or systemic PN target treatment has not been cleared from the body (eg, a period of 5 'half-lives'), whichever is longer. 13. Has received radiotherapy in the 6 weeks prior to start of study intervention or any prior radiotherapy directed at the target or non-target PN. 14. Receiving herbal supplements or medications known to be strong or moderate inhibitors of the CYP3A4 and CYP2C19 enzymes or inducers of the CYP3A4 enzyme unless such products can be safely discontinued at least 14 days or 5 half-lives (whichever is longer) before the first dose of study medication. 15. Inability to undergo MRI and/or contraindication for MRI examinations. Prosthesis or orthopaedic or dental braces that would interfere with volumetric analysis of target PN on MRI.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Selumetinib AUC0-12 Derived After Single Dose Administration | Pre-dose and 1, 2, 3, 4, 6, 8 and 10-12 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1) (each cycle is 28 days) | To determine the pharmacokinetics of selumetinib after administration of the selumetinib granule formulation |
| Adverse Events Graded by CTCAE Ver 5.0 | from screening until 30 days after last dose | To assess the safety and tolerability of the selumetinib granule formulation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Palatability Using the Parent-reported Observer Palatability Questionnaire | Twice daily (morning and evening), from the first day of study treatment (Cycle 1 Day 1) for one week, from Cycle 7 Day 1 for one week (each cycle is 28 days) | To assess the palatability of the selumetinib granule formulation |
| Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days) | To further evaluate the PK of the granule formulation. |
| Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days) | To further evaluate the PK of the granule formulation. |
| Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration | Pre-dose and 1, 2, 3, 4 and 6 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days) | To further evaluate the PK of the granule formulation. |
| Objective Response Rate | At screening, at week 17 (Cycle5 Day1), week 33 (Cycle9 Day1), week 49 (Cycle13 Day1), week 73 (Cycle19 Day1) and week 97 (Cycle25 Day1), end of treatment (each cycle is 28 days) | To evaluate the efficacy of the selumetinib granule formulation by assessment of Objective Response Rate |
| Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days) | To further evaluate the PK of the granule formulation. |
| Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days) | To further evaluate the PK of the granule formulation. |
| Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days) | To further evaluate the PK of the granule formulation. |
| Selumetinib and N-desmethyl Selumetinib AUC0-24 Derived After Single Dose Administration | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1) (each cycle is 28 days) | To further evaluate the PK of the granule formulation. |
| Selumetinib CL/F Derived After Single Dose Administration | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1) (each cycle is 28 days) | To further evaluate the PK of the granule formulation. |
| Selumetinib Vz/F Derived After Single Dose Administration | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1) (each cycle is 28 days) | To further evaluate the PK of the granule formulation. |
| Selumetinib t1/2λz Derived After Single Dose Administration | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1) (each cycle is 28 days) | To further evaluate the PK of the granule formulation. |
| Selumetinib and N-desmethyl Selumetinib Rac Cmax Derived After Multiple Dose Administration | Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days) | To further evaluate the PK of the granule formulation. |
| Selumetinib and N-desmethyl Selumetinib RacAUC0-12 Derived After Multiple Dose Administration | Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days) | To further evaluate the PK of the granule formulation. |
| Selumetinib CL/F Derived After Multiple Dose Administration | Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days) | To further evaluate the PK of the granule formulation. |
| Selumetinib Vss/F Derived After Multiple Dose Administration | Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days) | To further evaluate the PK of the granule formulation. |
| Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on Cycle 1 Day 1. Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days) | To further evaluate the PK of the granule formulation. |
| Parent to Metabolite Ratio for Cmax After Single and Multiple Dose Administration. | Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days) | To further evaluate the PK of the granule formulation. |
Countries
Germany, Italy, Japan, Netherlands, Russia, Spain, United States
Contacts
STUDY_DIRECTORStudy physician Study physician, MD
AstraZeneca
Participant flow
Recruitment details
The study is active, not recruiting and conducted in 7 countries with 39 patients who gave informed consent on or prior to 15 January 2024. Results are reported for the study at data cut-off 1 (DCO1) 08 April 2024.
Pre-assignment details
Eligible patients aged \>= 1 to \< 7 years at the time of informed consent with a diagnosis of NF1 with symptomatic inoperable PN fall into one of three cohorts: Global Cohort 1 (\>=4 to \<7 years), Global Cohort 2 (\>=1 to \<4 years), or Japan Cohort (\>=1 to \<7 years).
Participants by arm
| Arm | Count |
|---|---|
| Global Cohort 1 Global Cohort 1 (\>=4 to \<7 years) | 15 |
| Global Cohort 2 Global Cohort 2 (\>=1 to \<4 years) | 17 |
| Japan Cohort Japan Cohort (\>=1 to \<7 years) | 4 |
| Total | 36 |
Baseline characteristics
| Characteristic | Total | Global Cohort 2 | Japan Cohort | Global Cohort 1 |
|---|---|---|---|---|
| Age, Continuous | 3.78 years STANDARD_DEVIATION 1.681 | 2.49 years STANDARD_DEVIATION 0.819 | 4.43 years STANDARD_DEVIATION 2.3 | 5.08 years STANDARD_DEVIATION 1.101 |
| Body surface area group (m2) >=0.40 to <0.50 | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Body surface area group (m2) >=0.50 to <0.60 | 11 Participants | 11 Participants | 0 Participants | 0 Participants |
| Body surface area group (m2) >=0.60 to <0.70 | 11 Participants | 5 Participants | 3 Participants | 3 Participants |
| Body surface area group (m2) >=0.70 to <0.90 | 10 Participants | 0 Participants | 0 Participants | 10 Participants |
| Body surface area group (m2) >=0.90 to <1.10 | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Body surface area group (m2) >=1.10 to <=1.29 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| BSA | 0.652 m2 STANDARD_DEVIATION 0.1349 | 0.558 m2 STANDARD_DEVIATION 0.0603 | 0.605 m2 STANDARD_DEVIATION 0.1234 | 0.771 m2 STANDARD_DEVIATION 0.1073 |
| Country Germany | 9 Participants | 4 Participants | 0 Participants | 5 Participants |
| Country Italy | 9 Participants | 6 Participants | 0 Participants | 3 Participants |
| Country Japan | 4 Participants | 0 Participants | 4 Participants | 0 Participants |
| Country Russian Federation (the) | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Country Spain | 8 Participants | 4 Participants | 0 Participants | 4 Participants |
| Country United States of America (the) | 4 Participants | 3 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 15 Participants | 4 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants | 0 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Reported | 4 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 22 Participants | 13 Participants | 0 Participants | 9 Participants |
| Sex: Female, Male Female | 14 Participants | 7 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 22 Participants | 10 Participants | 2 Participants | 10 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 17 | 0 / 32 | 0 / 4 | 0 / 36 |
| other Total, other adverse events | 15 / 15 | 17 / 17 | 32 / 32 | 4 / 4 | 36 / 36 |
| serious Total, serious adverse events | 1 / 15 | 1 / 17 | 2 / 32 | 0 / 4 | 2 / 36 |
Outcome results
Primary
Adverse Events Graded by CTCAE Ver 5.0
To assess the safety and tolerability of the selumetinib granule formulation.
Time frame: from screening until 30 days after last dose
Primary
Selumetinib AUC0-12 Derived After Single Dose Administration
To determine the pharmacokinetics of selumetinib after administration of the selumetinib granule formulation
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8 and 10-12 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1) (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Japan Cohort was not considered for the primary endpoint analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Global Cohort 1 | Selumetinib AUC0-12 Derived After Single Dose Administration | 1902 h*ng/mL |
| Global Cohort 2 | Selumetinib AUC0-12 Derived After Single Dose Administration | 1699 h*ng/mL |
| Total in Global | Selumetinib AUC0-12 Derived After Single Dose Administration | 1790 h*ng/mL |
Secondary
Objective Response Rate
To evaluate the efficacy of the selumetinib granule formulation by assessment of Objective Response Rate
Time frame: At screening, at week 17 (Cycle5 Day1), week 33 (Cycle9 Day1), week 49 (Cycle13 Day1), week 73 (Cycle19 Day1) and week 97 (Cycle25 Day1), end of treatment (each cycle is 28 days)
Secondary
Palatability Using the Parent-reported Observer Palatability Questionnaire
To assess the palatability of the selumetinib granule formulation
Time frame: Twice daily (morning and evening), from the first day of study treatment (Cycle 1 Day 1) for one week, from Cycle 7 Day 1 for one week (each cycle is 28 days)
Secondary
Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration.
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on Cycle 1 Day 1. Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort 1 | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 1 Day 1: MPAUC0-6 | 0.07803 Ratio | Geometric Coefficient of Variation 18.27 |
| Global Cohort 1 | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 2 Day 1: MPAUC0-6 | 0.06036 Ratio | Geometric Coefficient of Variation 29.62 |
| Global Cohort 1 | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 2 Day 1: MPAUC0-12 | 0.06413 Ratio | Geometric Coefficient of Variation 29.74 |
| Global Cohort 1 | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 1 Day 1: MPAUC0-24 | 0.08209 Ratio | Geometric Coefficient of Variation 19.94 |
| Global Cohort 1 | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 1 Day 1: MPAUC0-12 | 0.08204 Ratio | Geometric Coefficient of Variation 17.91 |
| Global Cohort 2 | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 1 Day 1: MPAUC0-24 | 0.07516 Ratio | Geometric Coefficient of Variation 18.93 |
| Global Cohort 2 | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 2 Day 1: MPAUC0-6 | 0.06123 Ratio | Geometric Coefficient of Variation 26.61 |
| Global Cohort 2 | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 1 Day 1: MPAUC0-6 | 0.07379 Ratio | Geometric Coefficient of Variation 15.5 |
| Global Cohort 2 | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 1 Day 1: MPAUC0-12 | 0.07722 Ratio | Geometric Coefficient of Variation 17.19 |
| Global Cohort 2 | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 2 Day 1: MPAUC0-12 | 0.06429 Ratio | Geometric Coefficient of Variation 26.09 |
| Total in Global | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 1 Day 1: MPAUC0-6 | 0.07573 Ratio | Geometric Coefficient of Variation 16.76 |
| Total in Global | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 1 Day 1: MPAUC0-12 | 0.07960 Ratio | Geometric Coefficient of Variation 17.48 |
| Total in Global | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 1 Day 1: MPAUC0-24 | 0.07855 Ratio | Geometric Coefficient of Variation 19.59 |
| Total in Global | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 2 Day 1: MPAUC0-6 | 0.06078 Ratio | Geometric Coefficient of Variation 27.69 |
| Total in Global | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 2 Day 1: MPAUC0-12 | 0.06421 Ratio | Geometric Coefficient of Variation 27.42 |
| Japan Cohort | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 2 Day 1: MPAUC0-6 | 0.06934 Ratio | Geometric Coefficient of Variation 20.71 |
| Japan Cohort | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 1 Day 1: MPAUC0-12 | 0.07742 Ratio | Geometric Coefficient of Variation 14.05 |
| Japan Cohort | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 1 Day 1: MPAUC0-6 | 0.07386 Ratio | Geometric Coefficient of Variation 12.37 |
| Japan Cohort | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 1 Day 1: MPAUC0-24 | 0.07942 Ratio | Geometric Coefficient of Variation 7.881 |
| Japan Cohort | Parent-to-metabolite Ratio for AUC0-6, AUC0-12 and AUC0-24 After Single and Multiple Dose Administration. | Cycle 2 Day 1: MPAUC0-12 | 0.07339 Ratio | Geometric Coefficient of Variation 19.13 |
Secondary
Parent to Metabolite Ratio for Cmax After Single and Multiple Dose Administration.
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort 1 | Parent to Metabolite Ratio for Cmax After Single and Multiple Dose Administration. | Cycle 1 Day 1 | 0.07353 Ratio | Geometric Coefficient of Variation 20.68 |
| Global Cohort 1 | Parent to Metabolite Ratio for Cmax After Single and Multiple Dose Administration. | Cycle 2 Day 1 | 0.05635 Ratio | Geometric Coefficient of Variation 38.03 |
| Global Cohort 2 | Parent to Metabolite Ratio for Cmax After Single and Multiple Dose Administration. | Cycle 2 Day 1 | 0.05794 Ratio | Geometric Coefficient of Variation 26.08 |
| Global Cohort 2 | Parent to Metabolite Ratio for Cmax After Single and Multiple Dose Administration. | Cycle 1 Day 1 | 0.07044 Ratio | Geometric Coefficient of Variation 17.43 |
| Total in Global | Parent to Metabolite Ratio for Cmax After Single and Multiple Dose Administration. | Cycle 1 Day 1 | 0.07186 Ratio | Geometric Coefficient of Variation 18.76 |
| Total in Global | Parent to Metabolite Ratio for Cmax After Single and Multiple Dose Administration. | Cycle 2 Day 1 | 0.05711 Ratio | Geometric Coefficient of Variation 32.14 |
| Japan Cohort | Parent to Metabolite Ratio for Cmax After Single and Multiple Dose Administration. | Cycle 1 Day 1 | 0.06971 Ratio | Geometric Coefficient of Variation 23.12 |
| Japan Cohort | Parent to Metabolite Ratio for Cmax After Single and Multiple Dose Administration. | Cycle 2 Day 1 | 0.06706 Ratio | Geometric Coefficient of Variation 20.59 |
Secondary
Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 1902 h*ng/mL | Geometric Coefficient of Variation 24.19 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 156.1 h*ng/mL | Geometric Coefficient of Variation 25.76 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 3095 h*ng/mL | Geometric Coefficient of Variation 47.81 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 192.9 h*ng/mL | Geometric Coefficient of Variation 33.37 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 134.0 h*ng/mL | Geometric Coefficient of Variation 34.21 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 2114 h*ng/mL | Geometric Coefficient of Variation 49.23 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 135.9 h*ng/mL | Geometric Coefficient of Variation 33.82 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 1699 h*ng/mL | Geometric Coefficient of Variation 31.02 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 2575 h*ng/mL | Geometric Coefficient of Variation 52.23 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 144.6 h*ng/mL | Geometric Coefficient of Variation 30.69 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 161.9 h*ng/mL | Geometric Coefficient of Variation 37.97 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 1790 h*ng/mL | Geometric Coefficient of Variation 28.15 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 143.3 h*ng/mL | Geometric Coefficient of Variation 14.64 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 118.1 h*ng/mL | Geometric Coefficient of Variation 19.56 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 1526 h*ng/mL | Geometric Coefficient of Variation 25.09 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 1952 h*ng/mL | Geometric Coefficient of Variation 32.08 |
Secondary
Selumetinib and N-desmethyl Selumetinib AUC0-24 Derived After Single Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1) (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib AUC0-24 Derived After Single Dose Administration | Cycle 1 Day 1: Selumetinib | 2222 h*ng/mL | Geometric Coefficient of Variation 24.72 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib AUC0-24 Derived After Single Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 182.4 h*ng/mL | Geometric Coefficient of Variation 27.93 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib AUC0-24 Derived After Single Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 148.3 h*ng/mL | Geometric Coefficient of Variation 37.04 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib AUC0-24 Derived After Single Dose Administration | Cycle 1 Day 1: Selumetinib | 1942 h*ng/mL | Geometric Coefficient of Variation 29.73 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib AUC0-24 Derived After Single Dose Administration | Cycle 1 Day 1: Selumetinib | 2067 h*ng/mL | Geometric Coefficient of Variation 27.91 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib AUC0-24 Derived After Single Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 164.5 h*ng/mL | Geometric Coefficient of Variation 33.92 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib AUC0-24 Derived After Single Dose Administration | Cycle 1 Day 1: Selumetinib | 1568 h*ng/mL | Geometric Coefficient of Variation 7.648 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib AUC0-24 Derived After Single Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 129.8 h*ng/mL | Geometric Coefficient of Variation 13.54 |
Secondary
Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4 and 6 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 1516 h*ng/mL | Geometric Coefficient of Variation 30.42 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 118.3 h*ng/mL | Geometric Coefficient of Variation 31.4 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 2412 h*ng/mL | Geometric Coefficient of Variation 43.55 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 145.6 h*ng/mL | Geometric Coefficient of Variation 31.3 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 99.73 h*ng/mL | Geometric Coefficient of Variation 36.98 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 1672 h*ng/mL | Geometric Coefficient of Variation 48.14 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 102.4 h*ng/mL | Geometric Coefficient of Variation 35.17 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 1352 h*ng/mL | Geometric Coefficient of Variation 37.13 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 2021 h*ng/mL | Geometric Coefficient of Variation 49.4 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 108.0 h*ng/mL | Geometric Coefficient of Variation 35.04 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 122.8 h*ng/mL | Geometric Coefficient of Variation 37.71 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 1426 h*ng/mL | Geometric Coefficient of Variation 34.05 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 113.0 h*ng/mL | Geometric Coefficient of Variation 14.43 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 96.22 h*ng/mL | Geometric Coefficient of Variation 28.26 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 1303 h*ng/mL | Geometric Coefficient of Variation 32.65 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 1630 h*ng/mL | Geometric Coefficient of Variation 31.4 |
Secondary
Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 2208 h*ng/mL | Geometric Coefficient of Variation 24.81 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 167.7 h*ng/mL | Geometric Coefficient of Variation 32.98 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 2919 h*ng/mL | Geometric Coefficient of Variation 48.28 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 183.4 h*ng/mL | Geometric Coefficient of Variation 34.54 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 129.7 h*ng/mL | Geometric Coefficient of Variation 38.46 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 2031 h*ng/mL | Geometric Coefficient of Variation 49.45 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 128.9 h*ng/mL | Geometric Coefficient of Variation 34.3 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 1932 h*ng/mL | Geometric Coefficient of Variation 29.59 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 2450 h*ng/mL | Geometric Coefficient of Variation 52.12 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 146.2 h*ng/mL | Geometric Coefficient of Variation 37.93 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 154.7 h*ng/mL | Geometric Coefficient of Variation 38.8 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 2055 h*ng/mL | Geometric Coefficient of Variation 27.85 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 137.2 h*ng/mL | Geometric Coefficient of Variation 14.86 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 113.1 h*ng/mL | Geometric Coefficient of Variation 21.03 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 1709 h*ng/mL | Geometric Coefficient of Variation 20.33 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib AUClast Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 1887 h*ng/mL | Geometric Coefficient of Variation 32.22 |
Secondary
Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 551.1 ng/mL | Geometric Coefficient of Variation 44.21 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 40.53 ng/mL | Geometric Coefficient of Variation 45.76 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 843.4 ng/mL | Geometric Coefficient of Variation 42.69 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 47.53 ng/mL | Geometric Coefficient of Variation 38.92 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 32.73 ng/mL | Geometric Coefficient of Variation 52.62 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 502.6 ng/mL | Geometric Coefficient of Variation 58.59 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 29.12 ng/mL | Geometric Coefficient of Variation 47.81 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 464.7 ng/mL | Geometric Coefficient of Variation 54.05 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 656.9 ng/mL | Geometric Coefficient of Variation 58.01 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 36.14 ng/mL | Geometric Coefficient of Variation 49.99 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 37.52 ng/mL | Geometric Coefficient of Variation 50.63 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 503.0 ng/mL | Geometric Coefficient of Variation 49.58 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 43.20 ng/mL | Geometric Coefficient of Variation 19.56 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 43.11 ng/mL | Geometric Coefficient of Variation 54.06 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 618.4 ng/mL | Geometric Coefficient of Variation 76.36 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 644.2 ng/mL | Geometric Coefficient of Variation 23.68 |
Secondary
Selumetinib and N-desmethyl Selumetinib RacAUC0-12 Derived After Multiple Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib RacAUC0-12 Derived After Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 1.641 Ratio | Geometric Coefficient of Variation 54.51 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib RacAUC0-12 Derived After Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 1.221 Ratio | Geometric Coefficient of Variation 35.39 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib RacAUC0-12 Derived After Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 1.099 Ratio | Geometric Coefficient of Variation 53.72 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib RacAUC0-12 Derived After Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 1.289 Ratio | Geometric Coefficient of Variation 61.2 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib RacAUC0-12 Derived After Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 1.461 Ratio | Geometric Coefficient of Variation 58.23 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib RacAUC0-12 Derived After Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 1.163 Ratio | Geometric Coefficient of Variation 43.69 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib RacAUC0-12 Derived After Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 1.279 Ratio | Geometric Coefficient of Variation 53.18 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib RacAUC0-12 Derived After Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 1.213 Ratio | Geometric Coefficient of Variation 23.76 |
Secondary
Selumetinib and N-desmethyl Selumetinib Rac Cmax Derived After Multiple Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Rac Cmax Derived After Multiple Dose Administration | Cycle 2 Day 1, Selumetinib | 1.508 Ratio | Geometric Coefficient of Variation 56.59 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Rac Cmax Derived After Multiple Dose Administration | Cycle 2 Day 1, N-desmethyl selumetinib | 1.142 Ratio | Geometric Coefficient of Variation 61.34 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Rac Cmax Derived After Multiple Dose Administration | Cycle 2 Day 1, N-desmethyl selumetinib | 0.8837 Ratio | Geometric Coefficient of Variation 76.53 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Rac Cmax Derived After Multiple Dose Administration | Cycle 2 Day 1, Selumetinib | 1.104 Ratio | Geometric Coefficient of Variation 92.61 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Rac Cmax Derived After Multiple Dose Administration | Cycle 2 Day 1, Selumetinib | 1.304 Ratio | Geometric Coefficient of Variation 74.8 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Rac Cmax Derived After Multiple Dose Administration | Cycle 2 Day 1, N-desmethyl selumetinib | 1.014 Ratio | Geometric Coefficient of Variation 68.79 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Rac Cmax Derived After Multiple Dose Administration | Cycle 2 Day 1, Selumetinib | 1.042 Ratio | Geometric Coefficient of Variation 84.39 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Rac Cmax Derived After Multiple Dose Administration | Cycle 2 Day 1, N-desmethyl selumetinib | 1.002 Ratio | Geometric Coefficient of Variation 46.75 |
Secondary
Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 10.00 h |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 10.00 h |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 23.10 h |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 10.12 h |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 10.00 h |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 10.02 h |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 23.25 h |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 10.00 h |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 10.03 h |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 23.20 h |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 10.00 h |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 10.00 h |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 22.43 h |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 10.23 h |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 10.23 h |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Tlast Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 10.23 h |
Secondary
Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 1.83 h |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 1.83 h |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 2.00 h |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 2.00 h |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 2.02 h |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 1.97 h |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 2.01 h |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 2.00 h |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 2.00 h |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 2.00 h |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 2.00 h |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 1.97 h |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 1.56 h |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 2.47 h |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 2.47 h |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Tmax Derived After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 1.05 h |
Secondary
Selumetinib CL/F Derived After Multiple Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Global Cohort 1 | Selumetinib CL/F Derived After Multiple Dose Administration | 6.166 L/h | Geometric Coefficient of Variation 50.01 |
| Global Cohort 2 | Selumetinib CL/F Derived After Multiple Dose Administration | 6.051 L/h | Geometric Coefficient of Variation 48.38 |
| Total in Global | Selumetinib CL/F Derived After Multiple Dose Administration | 6.110 L/h | Geometric Coefficient of Variation 48.25 |
| Japan Cohort | Selumetinib CL/F Derived After Multiple Dose Administration | 6.943 L/h | Geometric Coefficient of Variation 26.97 |
Secondary
Selumetinib CL/F Derived After Single Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1) (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Global Cohort 1 | Selumetinib CL/F Derived After Single Dose Administration | 8.411 L/h | Geometric Coefficient of Variation 19.66 |
| Global Cohort 2 | Selumetinib CL/F Derived After Single Dose Administration | 6.167 L/h | Geometric Coefficient of Variation 36.79 |
| Total in Global | Selumetinib CL/F Derived After Single Dose Administration | 7.079 L/h | Geometric Coefficient of Variation 33.95 |
| Japan Cohort | Selumetinib CL/F Derived After Single Dose Administration | 8.757 L/h | Geometric Coefficient of Variation 2.452 |
Secondary
Selumetinib t1/2λz Derived After Single Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1) (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Global Cohort 1 | Selumetinib t1/2λz Derived After Single Dose Administration | 7.551 h | Geometric Coefficient of Variation 41.21 |
| Global Cohort 2 | Selumetinib t1/2λz Derived After Single Dose Administration | 7.230 h | Geometric Coefficient of Variation 58 |
| Total in Global | Selumetinib t1/2λz Derived After Single Dose Administration | 7.371 h | Geometric Coefficient of Variation 49.98 |
| Japan Cohort | Selumetinib t1/2λz Derived After Single Dose Administration | 8.486 h | Geometric Coefficient of Variation 49.4 |
Secondary
Selumetinib Vss/F Derived After Multiple Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Global Cohort 1 | Selumetinib Vss/F Derived After Multiple Dose Administration | 33.71 L | Geometric Coefficient of Variation 44.31 |
| Global Cohort 2 | Selumetinib Vss/F Derived After Multiple Dose Administration | 30.05 L | Geometric Coefficient of Variation 52.48 |
| Total in Global | Selumetinib Vss/F Derived After Multiple Dose Administration | 31.96 L | Geometric Coefficient of Variation 47.63 |
| Japan Cohort | Selumetinib Vss/F Derived After Multiple Dose Administration | 31.14 L | Geometric Coefficient of Variation 44.54 |
Secondary
Selumetinib Vz/F Derived After Single Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1) (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Global Cohort 1 | Selumetinib Vz/F Derived After Single Dose Administration | 91.63 L | Geometric Coefficient of Variation 33.64 |
| Global Cohort 2 | Selumetinib Vz/F Derived After Single Dose Administration | 64.33 L | Geometric Coefficient of Variation 44.81 |
| Total in Global | Selumetinib Vz/F Derived After Single Dose Administration | 75.28 L | Geometric Coefficient of Variation 43.86 |
| Japan Cohort | Selumetinib Vz/F Derived After Single Dose Administration | 107.2 L | Geometric Coefficient of Variation 50.91 |
Other Pre-specified
Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 2482 (h*ng/mL)/m2 | Geometric Coefficient of Variation 24.78 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 203.7 (h*ng/mL)/m2 | Geometric Coefficient of Variation 26.15 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 4041 (h*ng/mL)/m2 | Geometric Coefficient of Variation 54.06 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 247.5 (h*ng/mL)/m2 | Geometric Coefficient of Variation 34.34 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 242.6 (h*ng/mL)/m2 | Geometric Coefficient of Variation 33.67 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 3841 (h*ng/mL)/m2 | Geometric Coefficient of Variation 49.45 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 247.0 (h*ng/mL)/m2 | Geometric Coefficient of Variation 33.49 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 3074 (h*ng/mL)/m2 | Geometric Coefficient of Variation 33.19 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 3943 (h*ng/mL)/m2 | Geometric Coefficient of Variation 50.9 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 222.3 (h*ng/mL)/m2 | Geometric Coefficient of Variation 30.91 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 247.2 (h*ng/mL)/m2 | Geometric Coefficient of Variation 33.25 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 2784 (h*ng/mL)/m2 | Geometric Coefficient of Variation 31.12 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 238.4 (h*ng/mL)/m2 | Geometric Coefficient of Variation 22.82 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 198.9 (h*ng/mL)/m2 | Geometric Coefficient of Variation 41.19 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 2569 (h*ng/mL)/m2 | Geometric Coefficient of Variation 49.75 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 3249 (h*ng/mL)/m2 | Geometric Coefficient of Variation 27.13 |
Other Pre-specified
Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 1979 (h*ng/mL)/m2 | Geometric Coefficient of Variation 31.12 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 154.4 (h*ng/mL)/m2 | Geometric Coefficient of Variation 31.96 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 3150 (h*ng/mL)/m2 | Geometric Coefficient of Variation 48.62 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 190.1 (h*ng/mL)/m2 | Geometric Coefficient of Variation 33.01 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 180.5 (h*ng/mL)/m2 | Geometric Coefficient of Variation 38.38 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 3038 (h*ng/mL)/m2 | Geometric Coefficient of Variation 48.27 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 186.0 (h*ng/mL)/m2 | Geometric Coefficient of Variation 34.93 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 2446 (h*ng/mL)/m2 | Geometric Coefficient of Variation 40.2 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 3095 (h*ng/mL)/m2 | Geometric Coefficient of Variation 47.53 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 167.9 (h*ng/mL)/m2 | Geometric Coefficient of Variation 35.82 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 188.1 (h*ng/mL)/m2 | Geometric Coefficient of Variation 33.32 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 2217 (h*ng/mL)/m2 | Geometric Coefficient of Variation 37.31 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 188.1 (h*ng/mL)/m2 | Geometric Coefficient of Variation 26.55 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 162.0 (h*ng/mL)/m2 | Geometric Coefficient of Variation 51.74 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 2194 (h*ng/mL)/m2 | Geometric Coefficient of Variation 58.68 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 2713 (h*ng/mL)/m2 | Geometric Coefficient of Variation 28.07 |
Other Pre-specified
Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 2882 (h*ng/mL)/m2 | Geometric Coefficient of Variation 24.86 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 218.8 (h*ng/mL)/m2 | Geometric Coefficient of Variation 32.79 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 3811 (h*ng/mL)/m2 | Geometric Coefficient of Variation 54.07 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 239.5 (h*ng/mL)/m2 | Geometric Coefficient of Variation 37.31 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 234.8 (h*ng/mL)/m2 | Geometric Coefficient of Variation 37.15 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 3690 (h*ng/mL)/m2 | Geometric Coefficient of Variation 49.8 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 234.2 (h*ng/mL)/m2 | Geometric Coefficient of Variation 34.28 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 3496 (h*ng/mL)/m2 | Geometric Coefficient of Variation 31 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 3752 (h*ng/mL)/m2 | Geometric Coefficient of Variation 51.02 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 227.2 (h*ng/mL)/m2 | Geometric Coefficient of Variation 34.7 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 236.9 (h*ng/mL)/m2 | Geometric Coefficient of Variation 35.21 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 3196 (h*ng/mL)/m2 | Geometric Coefficient of Variation 29.58 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 228.4 (h*ng/mL)/m2 | Geometric Coefficient of Variation 23.68 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 190.5 (h*ng/mL)/m2 | Geometric Coefficient of Variation 42.43 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 2878 (h*ng/mL)/m2 | Geometric Coefficient of Variation 44.7 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 3141 (h*ng/mL)/m2 | Geometric Coefficient of Variation 27.58 |
Other Pre-specified
Selumetinib and N-desmethyl Selumetinib BSA Normalised Cmax After Single and Multiple Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib BSA Normalised Cmax After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 719.2 (ng/mL)/m2 | Geometric Coefficient of Variation 47.7 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib BSA Normalised Cmax After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 52.89 (ng/mL)/m2 | Geometric Coefficient of Variation 48.4 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib BSA Normalised Cmax After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 1101 (ng/mL)/m2 | Geometric Coefficient of Variation 46.84 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib BSA Normalised Cmax After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 62.06 (ng/mL)/m2 | Geometric Coefficient of Variation 39.05 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib BSA Normalised Cmax After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 59.23 (ng/mL)/m2 | Geometric Coefficient of Variation 52.39 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib BSA Normalised Cmax After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 913.1 (ng/mL)/m2 | Geometric Coefficient of Variation 56.39 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib BSA Normalised Cmax After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 52.90 (ng/mL)/m2 | Geometric Coefficient of Variation 45.74 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib BSA Normalised Cmax After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 840.9 (ng/mL)/m2 | Geometric Coefficient of Variation 55.12 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib BSA Normalised Cmax After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 1006 (ng/mL)/m2 | Geometric Coefficient of Variation 51.65 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib BSA Normalised Cmax After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 56.20 (ng/mL)/m2 | Geometric Coefficient of Variation 49.93 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib BSA Normalised Cmax After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 57.46 (ng/mL)/m2 | Geometric Coefficient of Variation 42.46 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib BSA Normalised Cmax After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 782.0 (ng/mL)/m2 | Geometric Coefficient of Variation 51.47 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib BSA Normalised Cmax After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 71.89 (ng/mL)/m2 | Geometric Coefficient of Variation 39.02 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib BSA Normalised Cmax After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 72.59 (ng/mL)/m2 | Geometric Coefficient of Variation 81.41 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib BSA Normalised Cmax After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 1041 (ng/mL)/m2 | Geometric Coefficient of Variation 110.3 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib BSA Normalised Cmax After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 1072 (ng/mL)/m2 | Geometric Coefficient of Variation 32.38 |
Other Pre-specified
Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-12 After Single and Multiple Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 97.73 (h*ng/mL)/mg | Geometric Coefficient of Variation 23.21 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 8.018 (h*ng/mL)/mg | Geometric Coefficient of Variation 27.48 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 162.2 (h*ng/mL)/mg | Geometric Coefficient of Variation 50.01 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 9.935 (h*ng/mL)/mg | Geometric Coefficient of Variation 30.66 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 10.31 (h*ng/mL)/mg | Geometric Coefficient of Variation 34.57 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 165.3 (h*ng/mL)/mg | Geometric Coefficient of Variation 48.38 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 10.63 (h*ng/mL)/mg | Geometric Coefficient of Variation 32.24 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 131.4 (h*ng/mL)/mg | Geometric Coefficient of Variation 33.44 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 163.7 (h*ng/mL)/mg | Geometric Coefficient of Variation 48.25 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 9.091 (h*ng/mL)/mg | Geometric Coefficient of Variation 33.36 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 10.27 (h*ng/mL)/mg | Geometric Coefficient of Variation 31.05 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 114.5 (h*ng/mL)/mg | Geometric Coefficient of Variation 32.58 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 10.57 (h*ng/mL)/mg | Geometric Coefficient of Variation 22.24 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 8.717 (h*ng/mL)/mg | Geometric Coefficient of Variation 37.98 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 112.6 (h*ng/mL)/mg | Geometric Coefficient of Variation 46.45 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-12 After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 144.0 (h*ng/mL)/mg | Geometric Coefficient of Variation 26.97 |
Other Pre-specified
Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-6 After Single and Multiple Dose Administration.
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-6 After Single and Multiple Dose Administration. | Cycle 1 Day 1: Selumetinib | 77.91 (h*ng/mL)/mg | Geometric Coefficient of Variation 30.23 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-6 After Single and Multiple Dose Administration. | Cycle 1 Day 1: N-desmethyl selumetinib | 6.079 (h*ng/mL)/mg | Geometric Coefficient of Variation 33.55 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-6 After Single and Multiple Dose Administration. | Cycle 2 Day 1: Selumetinib | 126.4 (h*ng/mL)/mg | Geometric Coefficient of Variation 44.74 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-6 After Single and Multiple Dose Administration. | Cycle 2 Day 1: N-desmethyl selumetinib | 7.630 (h*ng/mL)/mg | Geometric Coefficient of Variation 30.3 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-6 After Single and Multiple Dose Administration. | Cycle 1 Day 1: N-desmethyl selumetinib | 7.714 (h*ng/mL)/mg | Geometric Coefficient of Variation 39.05 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-6 After Single and Multiple Dose Administration. | Cycle 2 Day 1: Selumetinib | 130.7 (h*ng/mL)/mg | Geometric Coefficient of Variation 47.35 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-6 After Single and Multiple Dose Administration. | Cycle 2 Day 1: N-desmethyl selumetinib | 8.003 (h*ng/mL)/mg | Geometric Coefficient of Variation 33.93 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-6 After Single and Multiple Dose Administration. | Cycle 1 Day 1: Selumetinib | 104.5 (h*ng/mL)/mg | Geometric Coefficient of Variation 40.46 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-6 After Single and Multiple Dose Administration. | Cycle 2 Day 1: Selumetinib | 128.5 (h*ng/mL)/mg | Geometric Coefficient of Variation 45.14 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-6 After Single and Multiple Dose Administration. | Cycle 1 Day 1: N-desmethyl selumetinib | 6.906 (h*ng/mL)/mg | Geometric Coefficient of Variation 38.11 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-6 After Single and Multiple Dose Administration. | Cycle 2 Day 1: N-desmethyl selumetinib | 7.808 (h*ng/mL)/mg | Geometric Coefficient of Variation 31.58 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-6 After Single and Multiple Dose Administration. | Cycle 1 Day 1: Selumetinib | 91.20 (h*ng/mL)/mg | Geometric Coefficient of Variation 38.73 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-6 After Single and Multiple Dose Administration. | Cycle 2 Day 1: N-desmethyl selumetinib | 8.340 (h*ng/mL)/mg | Geometric Coefficient of Variation 26.01 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-6 After Single and Multiple Dose Administration. | Cycle 1 Day 1: N-desmethyl selumetinib | 7.099 (h*ng/mL)/mg | Geometric Coefficient of Variation 48.31 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-6 After Single and Multiple Dose Administration. | Cycle 1 Day 1: Selumetinib | 96.12 (h*ng/mL)/mg | Geometric Coefficient of Variation 55.13 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUC0-6 After Single and Multiple Dose Administration. | Cycle 2 Day 1: Selumetinib | 120.3 (h*ng/mL)/mg | Geometric Coefficient of Variation 27.94 |
Other Pre-specified
Selumetinib and N-desmethyl Selumetinib Dose Normalised AUClast After Single and Multiple Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUClast After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 113.4 (h*ng/mL)/mg | Geometric Coefficient of Variation 23.1 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUClast After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 8.615 (h*ng/mL)/mg | Geometric Coefficient of Variation 33.17 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUClast After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 152.9 (h*ng/mL)/mg | Geometric Coefficient of Variation 50.13 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUClast After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 9.613 (h*ng/mL)/mg | Geometric Coefficient of Variation 34.31 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUClast After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 10.03 (h*ng/mL)/mg | Geometric Coefficient of Variation 38.03 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUClast After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 158.8 (h*ng/mL)/mg | Geometric Coefficient of Variation 48.72 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUClast After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 10.08 (h*ng/mL)/mg | Geometric Coefficient of Variation 33 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUClast After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 149.4 (h*ng/mL)/mg | Geometric Coefficient of Variation 31.4 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUClast After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 155.7 (h*ng/mL)/mg | Geometric Coefficient of Variation 48.51 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUClast After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 9.349 (h*ng/mL)/mg | Geometric Coefficient of Variation 36.09 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUClast After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 9.834 (h*ng/mL)/mg | Geometric Coefficient of Variation 33.14 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUClast After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 131.5 (h*ng/mL)/mg | Geometric Coefficient of Variation 30.94 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUClast After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 10.12 (h*ng/mL)/mg | Geometric Coefficient of Variation 23.11 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUClast After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 8.347 (h*ng/mL)/mg | Geometric Coefficient of Variation 39.21 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUClast After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 126.1 (h*ng/mL)/mg | Geometric Coefficient of Variation 41.51 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Dose Normalised AUClast After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 139.2 (h*ng/mL)/mg | Geometric Coefficient of Variation 27.44 |
Other Pre-specified
Selumetinib and N-desmethyl Selumetinib Dose Normalised Cmax After Single and Multiple Dose Administration
To further evaluate the PK of the granule formulation.
Time frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)
Population: Pharmacokinetic analysis set was used for analysis. Some records were excluded for given visits and analytes due to missing concentration data, issues taking the medication and usage of prohibited medications.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Dose Normalised Cmax After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 28.31 (ng/mL)/mg | Geometric Coefficient of Variation 47.51 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Dose Normalised Cmax After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 2.082 (ng/mL)/mg | Geometric Coefficient of Variation 50.61 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Dose Normalised Cmax After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 44.20 (ng/mL)/mg | Geometric Coefficient of Variation 43.64 |
| Global Cohort 1 | Selumetinib and N-desmethyl Selumetinib Dose Normalised Cmax After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 2.491 (ng/mL)/mg | Geometric Coefficient of Variation 38.39 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Dose Normalised Cmax After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 2.532 (ng/mL)/mg | Geometric Coefficient of Variation 53.47 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Dose Normalised Cmax After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 39.29 (ng/mL)/mg | Geometric Coefficient of Variation 55.51 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Dose Normalised Cmax After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 2.276 (ng/mL)/mg | Geometric Coefficient of Variation 44.76 |
| Global Cohort 2 | Selumetinib and N-desmethyl Selumetinib Dose Normalised Cmax After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 35.94 (ng/mL)/mg | Geometric Coefficient of Variation 55.9 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Dose Normalised Cmax After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 41.76 (ng/mL)/mg | Geometric Coefficient of Variation 49.03 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Dose Normalised Cmax After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 2.312 (ng/mL)/mg | Geometric Coefficient of Variation 52.27 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Dose Normalised Cmax After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 2.385 (ng/mL)/mg | Geometric Coefficient of Variation 41.03 |
| Total in Global | Selumetinib and N-desmethyl Selumetinib Dose Normalised Cmax After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 32.17 (ng/mL)/mg | Geometric Coefficient of Variation 52.83 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Dose Normalised Cmax After Single and Multiple Dose Administration | Cycle 2 Day 1: N-desmethyl selumetinib | 3.187 (ng/mL)/mg | Geometric Coefficient of Variation 38.33 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Dose Normalised Cmax After Single and Multiple Dose Administration | Cycle 1 Day 1: N-desmethyl selumetinib | 3.181 (ng/mL)/mg | Geometric Coefficient of Variation 77.41 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Dose Normalised Cmax After Single and Multiple Dose Administration | Cycle 1 Day 1: Selumetinib | 45.63 (ng/mL)/mg | Geometric Coefficient of Variation 105.5 |
| Japan Cohort | Selumetinib and N-desmethyl Selumetinib Dose Normalised Cmax After Single and Multiple Dose Administration | Cycle 2 Day 1: Selumetinib | 47.52 (ng/mL)/mg | Geometric Coefficient of Variation 32.01 |