Healthy Volunteers
Conditions
Keywords
Bioavailability of Lenvatinib suspension, Palatability of Lenvatinib suspension, Lenvatinib, Lenvima, E7080, Capsule formulation, Healthy volunteers
Brief summary
The study will be conducted in adult healthy participants and will consist of two phases: Prerandomization and Randomization. The Prerandomization Phase will consist of 2 periods: a Screening Period and a Baseline Period. The Randomization Phase will consist of 2 Periods (each 6 days long) separated by a 1-day long Baseline Period and End of Treatment (EOT) Period. A total of 60 participants will be enrolled into one of three arms. Arms 1 and 3 consist of 2 sequences, and Arm 2 consists of 4 sequences (as this is an incomplete block design with 2 factors \[number of capsules and whether water or apple juice is used as vehicle\]). Each participant will be randomized into one of 8 sequences.
Interventions
DRUGLenvatinib
All participants will receive one single dose in each of the 2 treatment periods (total of 2 doses). The total duration of the treatment periods is 12 days (6 days per period) in healthy adult volunteers.
Sponsors
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male and female participants age greater than or equal to 18 years and less than or equal to 55 years old at time of informed consent 2. Nonsmokers or smokers who smoke no more than 10 cigarettes per day 3. BMI greater than or equal to 18 and less than or equal to 32 kg/m2 at screening 4. Adequate liver function, defined as: bilirubin less than or equal to 1.5 X the upper limit of normal (ULN), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and alanine aminotransferase (ALT) less than or equal to 1.5 X ULN 5. Adequate renal function defined as creatinine clearance greater than 70 mL/min calculated using the Cockcroft and Gault formula 6. Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin \[B-hCG\] test with a minimum sensitivity of 25 IU/L, or equivalent units of B-hCG. A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug. 7. All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing) 8. Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a double-barrier method \[such as condom plus diaphragm with spermicide\], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. If currently abstinent, the participant must agree to use a double-barrier method as described above if she becomes sexually active during the study period or for 30 days after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation. 9. Male participants must have had a successful vasectomy (confirmed azoospermia), or they and their female partners must meet the criteria above (ie, not of childbearing potential or practicing highly effective contraception throughout the study period and for 30 days after study drug discontinuation). No sperm donation is allowed during the study period and for 30 days after study drug discontinuation. 10. Provide written informed consent 11. Willing and able to comply with all aspects of the protocol
Exclusion criteria
1. Clinically significant illness that requires medical treatment within 8 weeks prior, or a clinically significant infection that requires medical treatment within 4 weeks prior to dosing 2. Evidence of disease that may influence the outcome of the study, within 4 weeks prior to dosing; eg, psychiatric disorders and disorders of the gastrointestinal (GI) tract, liver, kidney, respiratory system, endocrine system, hematological system, neurological system, or cardiovascular system, or participants who have a congenital abnormality in metabolism 3. Any history of surgery that may affect PK profiles of lenvatinib eg, hepatectomy, nephrotomy, digestive organ resection, at screening or baseline 4. Any clinically abnormal symptom or organ impairment found by medical history, physical examinations, vital signs, electrocardiogram (ECG) finding, or laboratory test results that requires medical treatment at screening or baseline 5. Prolonged QTcF interval (QTcF greater than 450 ms) demonstrated on ECG at screening or baseline 6. Known history of clinically significant drug allergy at Screening or Baseline 7. Known history of food allergies or presently experiencing significant seasonal or perennial allergy at Screening or Baseline 8. Known history of sensitivity to any of the components of the test products 9. Known to be human immunodeficiency virus (HIV) positive at screening 10. Active viral hepatitis (A, B, or C) as demonstrated by positive serology at screening 11. History of drug or alcohol dependency or abuse within the 2 years prior to screening, or those who have a positive urine drug test or breath alcohol test at Screening or Baseline 12. Engagement in strenuous exercise within 2 weeks prior to check-in (eg, marathon runners, weight lifters) 13. Any medical or other condition that would make the participant in the opinion of the investigator or sponsor, unsuitable for the study or who, in the opinion of the investigator, are not likely to complete the study for any reason 14. Intake of herbal preparations containing St. John's Wort within 4 weeks prior to dosing 15. Use of prescription drugs within 4 weeks prior to dosing 16. Intake of over-the-counter (OTC) medications within 2 weeks prior to dosing 17. Receipt of blood products within 4 weeks, or donation of blood within 8 weeks, or donation of plasma within 1 week prior to dosing
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | From date of first dose of study treatment to date of last dose of study treatment, up to approximately 2 months 10 days | Safety assessment consisted on monitoring and recording all treatment-emergent adverse events (TEAEs) and SAEs; as well as laboratory evaluations for hematology, blood chemistry, and urine values; periodic measurement of vital signs, electrocardiograms (ECGs); and physical examinations. A TEAE was defined as an adverse events that: 1) emerged during treatment and up to 7 days from the last treatment, having been absent before treatment or at baseline, 2) reemerged during treatment, having been present at Baseline but stopped before treatment, or 3) worsened in severity during treatment relative to the state before treatment, when continuous. |
| Area Under the Plasma Concentration-Time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC(0-t)) | Treatment Period 1: Day 1 (Visit 2), Day 2 (Visit 3), Days 3 to 6 (Visits 4 to 7); Treatment Period 2: Day 8 (Visit 8), Day 9 (Visit 9), Days 10 to 13 (Visits 10 to 13) | Blood samples were collected during each Treatment Period at predose and at 0.5, 1, 2, 3, 4, 8, 12, 16, 24, 48, 72, 96, and 120 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance liquid chromatography/tandem mass spectrometry (LC-MS/MS) method using a previously validated assay. The lower limit of quantitation (LLOQ) was 0.25 ng/mL. Plasma pharmacokinetics (PK) data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates of AUC(0-t), which were then summarized as the mean and standard deviation for all participants and expressed as hours·nanogram/milliliter (hr·ng/mL). |
| Area Under the Plasma Concentration-Time Curve From Zero to Infinity (AUC(0-inf)) | Treatment Period 1: Day 1 (Visit 2), Day 2 (Visit 3), Days 3 to 6 (Visits 4 to 7); Treatment Period 2: Day 8 (Visit 8), Day 9 (Visit 9), Days 10 to 13 (Visits 10 to 13) | Blood samples were collected during each Treatment Period at predose and at 0.5, 1, 2, 3, 4, 8, 12, 16, 24, 48, 72, 96, and 120 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates for the AUC(0-inf), which were then summarized as the mean and standard deviation for all participants and expressed as hr·ng/mL. |
| Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC(0-24)) | Treatment Period 1: Predose up to 24 hours post dose | Blood samples were collected during each Treatment Period at predose up to 24 hours post dose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates for the AUC(0-24), which were then summarized as the mean and standard deviation for all participants and expressed as hr·ng/mL. |
| Area Under the Plasma Concentration-Time Curve From Zero to 72 Hours (AUC(0-72)) | Treatment Period 1: Predose up to 72 hours postdose | Blood samples were collected during each Treatment Period at predose up to 72 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates for the AUC(0-72), which were then summarized as the mean and standard deviation for all participants and expressed as hr·ng/mL. |
| Apparent Clearance (CL/F) | Treatment Period 1: Day 1 (Visit 2), Day 2 (Visit 3), Days 3 to 6 (Visits 4 to 7); Treatment Period 2: Day 8 (Visit 8), Day 9 (Visit 9), Days 10 to 13 (Visits 10 to 13) | Blood samples were collected during each Treatment Period at predose and at 0.5, 1, 2, 3, 4, 8, 12, 16, 24, 48, 72, 96, and 120 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates for the CL/F, which were then summarized as the mean and standard deviation for all participants and expressed as liters/hour. |
| Apparent Volume of Distribution (Vz/F) | Treatment Period 1: Day 1 (Visit 2), Day 2 (Visit 3), Days 3 to 6 (Visits 4 to 7); Treatment Period 2: Day 8 (Visit 8), Day 9 (Visit 9), Days 10 to 13 (Visits 10 to 13) | Blood samples were collected during each Treatment Period at predose and at 0.5, 1, 2, 3, 4, 8, 12, 16, 24, 48, 72, 96, and 120 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates for the Vz/F, which were then summarized as the mean and standard deviation for all participants and expressed in liters (L). |
| Maximum Concentration (Cmax) of Lenvatinib in Plasma | Treatment Period 1: Day 1 (Visit 2), Day 2 (Visit 3), Days 3 to 6 (Visits 4 to 7); Treatment Period 2: Day 8 (Visit 8), Day 9 (Visit 9), Days 10 to 13 (Visits 10 to 13) | Blood samples were collected during each Treatment Period at predose and at 0.5, 1, 2, 3, 4, 8, 12, 16, 24, 48, 72, 96, and 120 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates of Cmax, which were then summarized as the mean and standard deviation for all participants and expressed as nanograms/milliliter (ng/mL). |
| Time Prior to the First Measureable Concentration of Lenvatinib (Tlag) | Treatment Period 1: Day 1 (Visit 2), Day 2 (Visit 3), Days 3 to 6 (Visits 4 to 7); Treatment Period 2: Day 8 (Visit 8), Day 9 (Visit 9), Days 10 to 13 (Visits 10 to 13) | Tlag was defined as the time delay between drug administration and the onset of drug absorption. Blood samples were collected during each Treatment Period at predose and at 0.5, 1, 2, 3, 4, 8, 12, 16, 24, 48, 72, 96, and 120 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates of tlag, which were then summarized as the median and full range for all participants and expressed in hours. |
| Time to Maximum Plasma Concentration (Tmax) | Treatment Period 1: Day 1 (Visit 2), Day 2 (Visit 3), Days 3 to 6 (Visits 4 to 7); Treatment Period 2: Day 8 (Visit 8), Day 9 (Visit 9), Days 10 to 13 (Visits 10 to 13) | Blood samples were collected during each Treatment Period at predose and at 0.5, 1, 2, 3, 4, 8, 12, 16, 24, 48, 72, 96, and 120 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates of tmax, which were then summarized as the median and full range for all participants and expressed in hours. |
| Terminal Elimination Phase Half-life (t1/2) | Treatment Period 1: Day 1 (Visit 2), Day 2 (Visit 3), Days 3 to 6 (Visits 4 to 7); Treatment Period 2: Day 8 (Visit 8), Day 9 (Visit 9), Days 10 to 13 (Visits 10 to 13) | Blood samples were collected during each Treatment Period at predose and at 0.5, 1, 2, 3, 4, 8, 12, 16, 24, 48, 72, 96, and 120 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates of t1/2, which were then summarized as the median and full range for all participants and expressed in hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summary Scores for Palatability of Lenvatinib | Treatment Period 1, Day 1 (Visit 2); Treatment Period 2, Day 8 (Visit 8) | A hedonic Visual Analog Scale (VAS) was used to assess taste likability or palatability between a) lenvatinib suspension formulated with water versus the capsule formulation, b) a lenvatinib suspension formulated with with apple juice versus one formulated with water, and c) a lenvatinib suspension formulated with water administered 23 hours versus 2 hours after preparation. All participants selected one face based on flavor, smell, sweetness, acidity, saltiness, bitterness, and texture or mouth feel for each formulation they consumed. Each face had an associated score (1: Very Bad (angry face), 2: Bad (sad face), 3: Maybe Good or Maybe Bad (neutral face), 4: Good (smiling face), 5: Very Good (laughing face)). The VAS hedonic scale scores were summarized using descriptive statistics separately for each arm by formulation (Arm 1), number of capsules (2 vs 5 capsules) and preparation type (water vs apple juice) (Arm 2), and time of administration relative to preparation (Arm 3). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: 11 mg Lenvatinib Suspension in Water On the mornings of Days 1 and 8, following an overnight fast of at least 10 hours, participants were administered lenvatinib (11 mg) suspension in water. No food was allowed for at least 4 hours post dose. Water was allowed ad libitum except for the period beginning 1 hour before and until 1 hour after lenvatinib administration. Treatments were administered at the same time on the 2 dosing days. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals. | 10 |
| Arm 1: 11 mg Lenvatinib Capsule With Water On the administered lenvatinib (11 mg) capsules with 240 mL (8 fluid ounces) of water. No food was allowed for at least 4 hours post dose. Water was allowed ad libitum except for the period beginning 1 hour before and until 1 hour after lenvatinib administration. Treatments were administered at the same time on the 2 dosing days. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals. | 10 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) On the mornings of Days 1 and 8 following an overnight fast of at least 10 hours, participants were administered a suspension of 5 capsules of lenvatinib (11 mg total) in water. No food was allowed for at least 4 hours post dose. Water was allowed ad libitum except for the period beginning 1 hour before and until 1 hour after lenvatinib administration. Treatments were administered at the same time on the 2 dosing days. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals. | 5 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) On the mornings of Days 1 and 8 following an overnight fast of at least 10 hours, participants were administered a suspension of 5 capsules of lenvatinib (11 mg total) in apple juice. No food was allowed for at least 4 hours post dose. Water was allowed ad libitum except for the period beginning 1 hour before and until 1 hour after lenvatinib administration. Treatments were administered at the same time on the 2 dosing days. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals. | 5 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) On the mornings of Days 1 and 8 following an overnight fast of at least 10 hours, participants were administered a suspension of 2 capsules of lenvatinib (11 mg total) in water. No food was allowed for at least 4 hours post dose. Water was allowed ad libitum except for the period beginning 1 hour before and until 1 hour after lenvatinib administration. Treatments were administered at the same time on the 2 dosing days. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals. | 5 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) On the mornings of Days 1 and 8 following an overnight fast of at least 10 hours, participants were administered a suspension of 2 capsules of lenvatinib (11 mg total) in apple juice. No food was allowed for at least 4 hours post dose. Water was allowed ad libitum except for the period beginning 1 hour before and until 1 hour after lenvatinib administration. Treatments were administered at the same time on the 2 dosing days. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals. | 5 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) On the mornings of Days 1 and 8, following an overnight fast of at least 10 hours, participants were administered lenvatinib (23 mg) suspension in water, which had been prepared 23 hours prior to administration. No food was allowed for at least 4 hours post dose. Water was allowed ad libitum except for the period beginning 1 hour before and until 1 hour after lenvatinib administration. Treatments were administered at the same time on the 2 dosing days. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals. | 10 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) On the mornings of Days 1 and 8, following an overnight fast of at least 10 hours, participants were administered lenvatinib (23 mg) suspension in water, which had been prepared 2 hours prior to administration. No food was allowed for at least 4 hours post dose. Water was allowed ad libitum except for the period beginning 1 hour before and until 1 hour after lenvatinib administration. Treatments were administered at the same time on the 2 dosing days. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals. | 10 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Treatment Period 2 | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 1 |
| Treatment Period 2 | Non compliance with alcohol prohibition | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period 2 | Use of proscribed medications | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Arm 1: 11 mg Lenvatinib Suspension in Water | Arm 1: 11 mg Lenvatinib Capsule With Water | Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized 18 to 65 years | 10 Participants | 10 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 10 Participants | 10 Participants | 60 Participants |
| Sex/Gender, Customized Female | 1 Participants | 3 Participants | 0 Participants | 2 Participants | 2 Participants | 2 Participants | 5 Participants | 3 Participants | 18 Participants |
| Sex/Gender, Customized Male | 9 Participants | 7 Participants | 5 Participants | 3 Participants | 3 Participants | 3 Participants | 5 Participants | 7 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 20 | 0 / 10 | 0 / 9 | 0 / 10 | 0 / 10 | 0 / 18 | 0 / 19 |
| other Total, other adverse events | 4 / 19 | 6 / 20 | 1 / 10 | 2 / 9 | 4 / 10 | 4 / 10 | 3 / 18 | 4 / 19 |
| serious Total, serious adverse events | 0 / 19 | 0 / 20 | 0 / 10 | 0 / 9 | 0 / 10 | 0 / 10 | 0 / 18 | 0 / 19 |
Outcome results
Primary
Apparent Clearance (CL/F)
Blood samples were collected during each Treatment Period at predose and at 0.5, 1, 2, 3, 4, 8, 12, 16, 24, 48, 72, 96, and 120 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates for the CL/F, which were then summarized as the mean and standard deviation for all participants and expressed as liters/hour.
Time frame: Treatment Period 1: Day 1 (Visit 2), Day 2 (Visit 3), Days 3 to 6 (Visits 4 to 7); Treatment Period 2: Day 8 (Visit 8), Day 9 (Visit 9), Days 10 to 13 (Visits 10 to 13)
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: 11 mg Lenvatinib Suspension in Water | Apparent Clearance (CL/F) | 9.34 L/hour | Standard Deviation 4.36 |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Apparent Clearance (CL/F) | 9.47 L/hour | Standard Deviation 4.45 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Apparent Clearance (CL/F) | 10.8 L/hour | Standard Deviation 1.73 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Apparent Clearance (CL/F) | 8.70 L/hour | Standard Deviation 3.44 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Apparent Clearance (CL/F) | 9.10 L/hour | Standard Deviation 3.07 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Apparent Clearance (CL/F) | 10.9 L/hour | Standard Deviation 1.61 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Apparent Clearance (CL/F) | 8.46 L/hour | Standard Deviation 2.65 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Apparent Clearance (CL/F) | 7.73 L/hour | Standard Deviation 2.19 |
Primary
Apparent Volume of Distribution (Vz/F)
Blood samples were collected during each Treatment Period at predose and at 0.5, 1, 2, 3, 4, 8, 12, 16, 24, 48, 72, 96, and 120 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates for the Vz/F, which were then summarized as the mean and standard deviation for all participants and expressed in liters (L).
Time frame: Treatment Period 1: Day 1 (Visit 2), Day 2 (Visit 3), Days 3 to 6 (Visits 4 to 7); Treatment Period 2: Day 8 (Visit 8), Day 9 (Visit 9), Days 10 to 13 (Visits 10 to 13)
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: 11 mg Lenvatinib Suspension in Water | Apparent Volume of Distribution (Vz/F) | 301 Liters | Standard Deviation 159 |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Apparent Volume of Distribution (Vz/F) | 296 Liters | Standard Deviation 123 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Apparent Volume of Distribution (Vz/F) | 356 Liters | Standard Deviation 74 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Apparent Volume of Distribution (Vz/F) | 317 Liters | Standard Deviation 131 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Apparent Volume of Distribution (Vz/F) | 312 Liters | Standard Deviation 122 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Apparent Volume of Distribution (Vz/F) | 360 Liters | Standard Deviation 103 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Apparent Volume of Distribution (Vz/F) | 247 Liters | Standard Deviation 95.7 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Apparent Volume of Distribution (Vz/F) | 238 Liters | Standard Deviation 122 |
Primary
Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC(0-24))
Blood samples were collected during each Treatment Period at predose up to 24 hours post dose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates for the AUC(0-24), which were then summarized as the mean and standard deviation for all participants and expressed as hr·ng/mL.
Time frame: Treatment Period 1: Predose up to 24 hours post dose
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: 11 mg Lenvatinib Suspension in Water | Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC(0-24)) | 1060 h·ng/mL | Standard Deviation 377 |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC(0-24)) | 1050 h·ng/mL | Standard Deviation 383 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC(0-24)) | 815 h·ng/mL | Standard Deviation 136 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC(0-24)) | 1150 h·ng/mL | Standard Deviation 564 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC(0-24)) | 1070 h·ng/mL | Standard Deviation 415 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC(0-24)) | 804 h·ng/mL | Standard Deviation 136 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC(0-24)) | 2540 h·ng/mL | Standard Deviation 785 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC(0-24)) | 2720 h·ng/mL | Standard Deviation 858 |
Primary
Area Under the Plasma Concentration-Time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC(0-t))
Blood samples were collected during each Treatment Period at predose and at 0.5, 1, 2, 3, 4, 8, 12, 16, 24, 48, 72, 96, and 120 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance liquid chromatography/tandem mass spectrometry (LC-MS/MS) method using a previously validated assay. The lower limit of quantitation (LLOQ) was 0.25 ng/mL. Plasma pharmacokinetics (PK) data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates of AUC(0-t), which were then summarized as the mean and standard deviation for all participants and expressed as hours·nanogram/milliliter (hr·ng/mL).
Time frame: Treatment Period 1: Day 1 (Visit 2), Day 2 (Visit 3), Days 3 to 6 (Visits 4 to 7); Treatment Period 2: Day 8 (Visit 8), Day 9 (Visit 9), Days 10 to 13 (Visits 10 to 13)
Population: The PK Analysis Set was the group of subjects who had sufficient PK data for at least 1 PK parameter to be derived. Subjects with predose lenvatinib concentration \>5% of their own Cmax, and subjects who experienced emesis at or before 2x median tmax were excluded from data analysis for bioavailability.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: 11 mg Lenvatinib Suspension in Water | Area Under the Plasma Concentration-Time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC(0-t)) | 1330 hr·ng/mL | Standard Deviation 452 |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Area Under the Plasma Concentration-Time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC(0-t)) | 1340 hr·ng/mL | Standard Deviation 482 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Area Under the Plasma Concentration-Time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC(0-t)) | 1020 hr·ng/mL | Standard Deviation 172 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Area Under the Plasma Concentration-Time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC(0-t)) | 1500 hr·ng/mL | Standard Deviation 706 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Area Under the Plasma Concentration-Time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC(0-t)) | 1340 hr·ng/mL | Standard Deviation 519 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Area Under the Plasma Concentration-Time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC(0-t)) | 1010 hr·ng/mL | Standard Deviation 160 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Area Under the Plasma Concentration-Time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC(0-t)) | 3010 hr·ng/mL | Standard Deviation 919 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Area Under the Plasma Concentration-Time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC(0-t)) | 3210 hr·ng/mL | Standard Deviation 1040 |
Primary
Area Under the Plasma Concentration-Time Curve From Zero to 72 Hours (AUC(0-72))
Blood samples were collected during each Treatment Period at predose up to 72 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates for the AUC(0-72), which were then summarized as the mean and standard deviation for all participants and expressed as hr·ng/mL.
Time frame: Treatment Period 1: Predose up to 72 hours postdose
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: 11 mg Lenvatinib Suspension in Water | Area Under the Plasma Concentration-Time Curve From Zero to 72 Hours (AUC(0-72)) | 1280 hr·ng/mL | Standard Deviation 437 |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Area Under the Plasma Concentration-Time Curve From Zero to 72 Hours (AUC(0-72)) | 1290 hr·ng/mL | Standard Deviation 466 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Area Under the Plasma Concentration-Time Curve From Zero to 72 Hours (AUC(0-72)) | 987 hr·ng/mL | Standard Deviation 164 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Area Under the Plasma Concentration-Time Curve From Zero to 72 Hours (AUC(0-72)) | 1430 hr·ng/mL | Standard Deviation 668 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Area Under the Plasma Concentration-Time Curve From Zero to 72 Hours (AUC(0-72)) | 1290 hr·ng/mL | Standard Deviation 500 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Area Under the Plasma Concentration-Time Curve From Zero to 72 Hours (AUC(0-72)) | 971 hr·ng/mL | Standard Deviation 152 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Area Under the Plasma Concentration-Time Curve From Zero to 72 Hours (AUC(0-72)) | 2930 hr·ng/mL | Standard Deviation 887 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Area Under the Plasma Concentration-Time Curve From Zero to 72 Hours (AUC(0-72)) | 3130 hr·ng/mL | Standard Deviation 1010 |
Primary
Area Under the Plasma Concentration-Time Curve From Zero to Infinity (AUC(0-inf))
Blood samples were collected during each Treatment Period at predose and at 0.5, 1, 2, 3, 4, 8, 12, 16, 24, 48, 72, 96, and 120 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates for the AUC(0-inf), which were then summarized as the mean and standard deviation for all participants and expressed as hr·ng/mL.
Time frame: Treatment Period 1: Day 1 (Visit 2), Day 2 (Visit 3), Days 3 to 6 (Visits 4 to 7); Treatment Period 2: Day 8 (Visit 8), Day 9 (Visit 9), Days 10 to 13 (Visits 10 to 13)
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: 11 mg Lenvatinib Suspension in Water | Area Under the Plasma Concentration-Time Curve From Zero to Infinity (AUC(0-inf)) | 1360 hr·ng/mL | Standard Deviation 456 |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Area Under the Plasma Concentration-Time Curve From Zero to Infinity (AUC(0-inf)) | 1360 hr·ng/mL | Standard Deviation 490 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Area Under the Plasma Concentration-Time Curve From Zero to Infinity (AUC(0-inf)) | 1040 hr·ng/mL | Standard Deviation 177 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Area Under the Plasma Concentration-Time Curve From Zero to Infinity (AUC(0-inf)) | 1530 hr·ng/mL | Standard Deviation 720 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Area Under the Plasma Concentration-Time Curve From Zero to Infinity (AUC(0-inf)) | 1370 hr·ng/mL | Standard Deviation 532 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Area Under the Plasma Concentration-Time Curve From Zero to Infinity (AUC(0-inf)) | 1030 hr·ng/mL | Standard Deviation 161 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Area Under the Plasma Concentration-Time Curve From Zero to Infinity (AUC(0-inf)) | 2970 hr·ng/mL | Standard Deviation 910 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Area Under the Plasma Concentration-Time Curve From Zero to Infinity (AUC(0-inf)) | 3240 hr·ng/mL | Standard Deviation 1050 |
Primary
Maximum Concentration (Cmax) of Lenvatinib in Plasma
Blood samples were collected during each Treatment Period at predose and at 0.5, 1, 2, 3, 4, 8, 12, 16, 24, 48, 72, 96, and 120 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates of Cmax, which were then summarized as the mean and standard deviation for all participants and expressed as nanograms/milliliter (ng/mL).
Time frame: Treatment Period 1: Day 1 (Visit 2), Day 2 (Visit 3), Days 3 to 6 (Visits 4 to 7); Treatment Period 2: Day 8 (Visit 8), Day 9 (Visit 9), Days 10 to 13 (Visits 10 to 13)
Population: Pharmacokinetic (PK) analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: 11 mg Lenvatinib Suspension in Water | Maximum Concentration (Cmax) of Lenvatinib in Plasma | 133 ng/mL | Standard Deviation 52.5 |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Maximum Concentration (Cmax) of Lenvatinib in Plasma | 126 ng/mL | Standard Deviation 44.9 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Maximum Concentration (Cmax) of Lenvatinib in Plasma | 115 ng/mL | Standard Deviation 22.9 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Maximum Concentration (Cmax) of Lenvatinib in Plasma | 150 ng/mL | Standard Deviation 65.2 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Maximum Concentration (Cmax) of Lenvatinib in Plasma | 138 ng/mL | Standard Deviation 61.3 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Maximum Concentration (Cmax) of Lenvatinib in Plasma | 105 ng/mL | Standard Deviation 21.2 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Maximum Concentration (Cmax) of Lenvatinib in Plasma | 358 ng/mL | Standard Deviation 128 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Maximum Concentration (Cmax) of Lenvatinib in Plasma | 375 ng/mL | Standard Deviation 134 |
Primary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib
Safety assessment consisted on monitoring and recording all treatment-emergent adverse events (TEAEs) and SAEs; as well as laboratory evaluations for hematology, blood chemistry, and urine values; periodic measurement of vital signs, electrocardiograms (ECGs); and physical examinations. A TEAE was defined as an adverse events that: 1) emerged during treatment and up to 7 days from the last treatment, having been absent before treatment or at baseline, 2) reemerged during treatment, having been present at Baseline but stopped before treatment, or 3) worsened in severity during treatment relative to the state before treatment, when continuous.
Time frame: From date of first dose of study treatment to date of last dose of study treatment, up to approximately 2 months 10 days
Population: Safety Analysis Set was the group of subjects who received at least 1 dose of study drug and had at least 1 postdose safety assessment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: 11 mg Lenvatinib Suspension in Water | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | TEAEs | 4 Participants |
| Arm 1: 11 mg Lenvatinib Suspension in Water | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Treatment-related TEAEs | 4 Participants |
| Arm 1: 11 mg Lenvatinib Suspension in Water | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Severe TEAEs | 0 Participants |
| Arm 1: 11 mg Lenvatinib Suspension in Water | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Serious TEAEs | 0 Participants |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Serious TEAEs | 0 Participants |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Treatment-related TEAEs | 6 Participants |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | TEAEs | 6 Participants |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Severe TEAEs | 0 Participants |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | TEAEs | 1 Participants |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Serious TEAEs | 0 Participants |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Treatment-related TEAEs | 0 Participants |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Severe TEAEs | 0 Participants |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | TEAEs | 2 Participants |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Treatment-related TEAEs | 1 Participants |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Severe TEAEs | 0 Participants |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Serious TEAEs | 0 Participants |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Serious TEAEs | 0 Participants |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Severe TEAEs | 0 Participants |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Treatment-related TEAEs | 2 Participants |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | TEAEs | 4 Participants |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Serious TEAEs | 0 Participants |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Severe TEAEs | 0 Participants |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Treatment-related TEAEs | 1 Participants |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | TEAEs | 4 Participants |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Serious TEAEs | 0 Participants |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | TEAEs | 3 Participants |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Severe TEAEs | 0 Participants |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Treatment-related TEAEs | 3 Participants |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Treatment-related TEAEs | 2 Participants |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Severe TEAEs | 0 Participants |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | Serious TEAEs | 0 Participants |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib | TEAEs | 4 Participants |
Primary
Terminal Elimination Phase Half-life (t1/2)
Blood samples were collected during each Treatment Period at predose and at 0.5, 1, 2, 3, 4, 8, 12, 16, 24, 48, 72, 96, and 120 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates of t1/2, which were then summarized as the median and full range for all participants and expressed in hours.
Time frame: Treatment Period 1: Day 1 (Visit 2), Day 2 (Visit 3), Days 3 to 6 (Visits 4 to 7); Treatment Period 2: Day 8 (Visit 8), Day 9 (Visit 9), Days 10 to 13 (Visits 10 to 13)
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: 11 mg Lenvatinib Suspension in Water | Terminal Elimination Phase Half-life (t1/2) | 22.7 Hours | Standard Deviation 6.09 |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Terminal Elimination Phase Half-life (t1/2) | 22.4 Hours | Standard Deviation 4.67 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Terminal Elimination Phase Half-life (t1/2) | 23.2 Hours | Standard Deviation 5.67 |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Terminal Elimination Phase Half-life (t1/2) | 25.5 Hours | Standard Deviation 4.27 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Terminal Elimination Phase Half-life (t1/2) | 24.1 Hours | Standard Deviation 5.05 |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Terminal Elimination Phase Half-life (t1/2) | 23.1 Hours | Standard Deviation 6.15 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Terminal Elimination Phase Half-life (t1/2) | 20.4 Hours | Standard Deviation 4.51 |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Terminal Elimination Phase Half-life (t1/2) | 21.5 Hours | Standard Deviation 7.35 |
Primary
Time Prior to the First Measureable Concentration of Lenvatinib (Tlag)
Tlag was defined as the time delay between drug administration and the onset of drug absorption. Blood samples were collected during each Treatment Period at predose and at 0.5, 1, 2, 3, 4, 8, 12, 16, 24, 48, 72, 96, and 120 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates of tlag, which were then summarized as the median and full range for all participants and expressed in hours.
Time frame: Treatment Period 1: Day 1 (Visit 2), Day 2 (Visit 3), Days 3 to 6 (Visits 4 to 7); Treatment Period 2: Day 8 (Visit 8), Day 9 (Visit 9), Days 10 to 13 (Visits 10 to 13)
Population: PK analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: 11 mg Lenvatinib Suspension in Water | Time Prior to the First Measureable Concentration of Lenvatinib (Tlag) | 0.00 Hours |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Time Prior to the First Measureable Concentration of Lenvatinib (Tlag) | 0.00 Hours |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Time Prior to the First Measureable Concentration of Lenvatinib (Tlag) | 0.00 Hours |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Time Prior to the First Measureable Concentration of Lenvatinib (Tlag) | 0.00 Hours |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Time Prior to the First Measureable Concentration of Lenvatinib (Tlag) | 0.00 Hours |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Time Prior to the First Measureable Concentration of Lenvatinib (Tlag) | 0.00 Hours |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Time Prior to the First Measureable Concentration of Lenvatinib (Tlag) | 0.00 Hours |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Time Prior to the First Measureable Concentration of Lenvatinib (Tlag) | 0.00 Hours |
Primary
Time to Maximum Plasma Concentration (Tmax)
Blood samples were collected during each Treatment Period at predose and at 0.5, 1, 2, 3, 4, 8, 12, 16, 24, 48, 72, 96, and 120 hours postdose. Plasma concentrations of lenvatinib were quantified by a high-performance LC-MS/MS method using a previously validated assay. The LLOQ was 0.25 ng/mL. Plasma PK data were analyzed using a non-compartmental analysis approach to obtain individual participant estimates of tmax, which were then summarized as the median and full range for all participants and expressed in hours.
Time frame: Treatment Period 1: Day 1 (Visit 2), Day 2 (Visit 3), Days 3 to 6 (Visits 4 to 7); Treatment Period 2: Day 8 (Visit 8), Day 9 (Visit 9), Days 10 to 13 (Visits 10 to 13)
Population: PK analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: 11 mg Lenvatinib Suspension in Water | Time to Maximum Plasma Concentration (Tmax) | 3.00 Hours |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Time to Maximum Plasma Concentration (Tmax) | 3.00 Hours |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Time to Maximum Plasma Concentration (Tmax) | 2.52 Hours |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Time to Maximum Plasma Concentration (Tmax) | 3.00 Hours |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Time to Maximum Plasma Concentration (Tmax) | 2.50 Hours |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Time to Maximum Plasma Concentration (Tmax) | 2.00 Hours |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Time to Maximum Plasma Concentration (Tmax) | 2.00 Hours |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Time to Maximum Plasma Concentration (Tmax) | 2.00 Hours |
Secondary
Summary Scores for Palatability of Lenvatinib
A hedonic Visual Analog Scale (VAS) was used to assess taste likability or palatability between a) lenvatinib suspension formulated with water versus the capsule formulation, b) a lenvatinib suspension formulated with with apple juice versus one formulated with water, and c) a lenvatinib suspension formulated with water administered 23 hours versus 2 hours after preparation. All participants selected one face based on flavor, smell, sweetness, acidity, saltiness, bitterness, and texture or mouth feel for each formulation they consumed. Each face had an associated score (1: Very Bad (angry face), 2: Bad (sad face), 3: Maybe Good or Maybe Bad (neutral face), 4: Good (smiling face), 5: Very Good (laughing face)). The VAS hedonic scale scores were summarized using descriptive statistics separately for each arm by formulation (Arm 1), number of capsules (2 vs 5 capsules) and preparation type (water vs apple juice) (Arm 2), and time of administration relative to preparation (Arm 3).
Time frame: Treatment Period 1, Day 1 (Visit 2); Treatment Period 2, Day 8 (Visit 8)
Population: The Palatability Analysis Set was the group of subjects who received at least 1 dose of study drug and completed the visual analog scale (VAS) in at least one treatment period.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1: 11 mg Lenvatinib Suspension in Water | Summary Scores for Palatability of Lenvatinib | Saltiness Score | 3.0 Score on a scale |
| Arm 1: 11 mg Lenvatinib Suspension in Water | Summary Scores for Palatability of Lenvatinib | Bitterness Score | 3.0 Score on a scale |
| Arm 1: 11 mg Lenvatinib Suspension in Water | Summary Scores for Palatability of Lenvatinib | Sweetness Score | 3.0 Score on a scale |
| Arm 1: 11 mg Lenvatinib Suspension in Water | Summary Scores for Palatability of Lenvatinib | Flavor Score | 3.0 Score on a scale |
| Arm 1: 11 mg Lenvatinib Suspension in Water | Summary Scores for Palatability of Lenvatinib | Smell Score | 4.0 Score on a scale |
| Arm 1: 11 mg Lenvatinib Suspension in Water | Summary Scores for Palatability of Lenvatinib | Acidity Score | 3.0 Score on a scale |
| Arm 1: 11 mg Lenvatinib Suspension in Water | Summary Scores for Palatability of Lenvatinib | Texture or Mouth feel Score | 3.0 Score on a scale |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Summary Scores for Palatability of Lenvatinib | Texture or Mouth feel Score | 3.5 Score on a scale |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Summary Scores for Palatability of Lenvatinib | Saltiness Score | 4.0 Score on a scale |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Summary Scores for Palatability of Lenvatinib | Smell Score | 4.0 Score on a scale |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Summary Scores for Palatability of Lenvatinib | Sweetness Score | 3.0 Score on a scale |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Summary Scores for Palatability of Lenvatinib | Acidity Score | 4.0 Score on a scale |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Summary Scores for Palatability of Lenvatinib | Flavor Score | 4.0 Score on a scale |
| Arm 1: 11 mg Lenvatinib Capsule With Water | Summary Scores for Palatability of Lenvatinib | Bitterness Score | 3.5 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Summary Scores for Palatability of Lenvatinib | Saltiness Score | 3.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Summary Scores for Palatability of Lenvatinib | Texture or Mouth feel Score | 2.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Summary Scores for Palatability of Lenvatinib | Acidity Score | 3.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Summary Scores for Palatability of Lenvatinib | Smell Score | 3.5 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Summary Scores for Palatability of Lenvatinib | Flavor Score | 3.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Summary Scores for Palatability of Lenvatinib | Bitterness Score | 3.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Water) | Summary Scores for Palatability of Lenvatinib | Sweetness Score | 3.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Summary Scores for Palatability of Lenvatinib | Acidity Score | 3.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Summary Scores for Palatability of Lenvatinib | Texture or Mouth feel Score | 4.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Summary Scores for Palatability of Lenvatinib | Smell Score | 4.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Summary Scores for Palatability of Lenvatinib | Bitterness Score | 3.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Summary Scores for Palatability of Lenvatinib | Sweetness Score | 4.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Summary Scores for Palatability of Lenvatinib | Flavor Score | 4.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 5 Capsules in Juice) | Summary Scores for Palatability of Lenvatinib | Saltiness Score | 4.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Summary Scores for Palatability of Lenvatinib | Acidity Score | 2.5 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Summary Scores for Palatability of Lenvatinib | Flavor Score | 2.5 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Summary Scores for Palatability of Lenvatinib | Smell Score | 4.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Summary Scores for Palatability of Lenvatinib | Sweetness Score | 2.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Summary Scores for Palatability of Lenvatinib | Saltiness Score | 3.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Summary Scores for Palatability of Lenvatinib | Bitterness Score | 3.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Water) | Summary Scores for Palatability of Lenvatinib | Texture or Mouth feel Score | 3.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Summary Scores for Palatability of Lenvatinib | Acidity Score | 4.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Summary Scores for Palatability of Lenvatinib | Texture or Mouth feel Score | 4.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Summary Scores for Palatability of Lenvatinib | Saltiness Score | 4.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Summary Scores for Palatability of Lenvatinib | Sweetness Score | 4.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Summary Scores for Palatability of Lenvatinib | Bitterness Score | 3.5 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Summary Scores for Palatability of Lenvatinib | Smell Score | 4.0 Score on a scale |
| Arm 2: 11 mg Lenvatinib (Suspension of 2 Capsules in Juice) | Summary Scores for Palatability of Lenvatinib | Flavor Score | 4.0 Score on a scale |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Summary Scores for Palatability of Lenvatinib | Smell Score | 3.0 Score on a scale |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Summary Scores for Palatability of Lenvatinib | Flavor Score | 2.0 Score on a scale |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Summary Scores for Palatability of Lenvatinib | Bitterness Score | 3.0 Score on a scale |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Summary Scores for Palatability of Lenvatinib | Saltiness Score | 3.0 Score on a scale |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Summary Scores for Palatability of Lenvatinib | Texture or Mouth feel Score | 2.0 Score on a scale |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Summary Scores for Palatability of Lenvatinib | Sweetness Score | 2.0 Score on a scale |
| Arm 3: 23 mg Lenvatinib Suspension in Water (23 Hours) | Summary Scores for Palatability of Lenvatinib | Acidity Score | 3.0 Score on a scale |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Summary Scores for Palatability of Lenvatinib | Texture or Mouth feel Score | 2.0 Score on a scale |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Summary Scores for Palatability of Lenvatinib | Acidity Score | 3.0 Score on a scale |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Summary Scores for Palatability of Lenvatinib | Bitterness Score | 2.0 Score on a scale |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Summary Scores for Palatability of Lenvatinib | Flavor Score | 2.0 Score on a scale |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Summary Scores for Palatability of Lenvatinib | Sweetness Score | 2.0 Score on a scale |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Summary Scores for Palatability of Lenvatinib | Saltiness Score | 4.0 Score on a scale |
| Arm 3: 23 mg Lenvatinib Suspension in Water (2 Hours) | Summary Scores for Palatability of Lenvatinib | Smell Score | 3.0 Score on a scale |