Healthy Volunteers
Conditions
Keywords
Bioequivalence, Lenvatinib, Healthy Volunteers, Lenvima, E7080
Brief summary
This will be a randomized, single dose, open-label, three-treatment period crossover study in healthy participants to determine whether 2 test lots of 10-mg capsules that vary by the level of lenvatinib Type-C crystal are bioequivalent to a reference lot of 10-mg capsules.
Detailed description
The study will consist of 2 phases: Prerandomization and Randomization. The Prerandomization Phase will have 2 periods: Screening and Baseline. The Randomization Phase will consist of three 6-day long Treatment Periods with each Treatment Period separated by a 1-day long Baseline. Sixty participants will be evenly randomized to 1 of 6 possible treatment sequences (A, B, C, D, E, or F). The 3 treatments vary by the level of crystalline polymorph Type-C present in the drug product batch used in each arm, respectively: Treatment 1 - low Type-C crystal level less than 12%; Treatment 2 - reference Type-C crystal level 12% to 26%; and Treatment 3 - high Type-C crystal level greater than 26%.
Interventions
DRUGLenvatinib 10 mg
Treatment 1: low Type-C crystal level \<12% Treatment 2: reference\* Type-C crystal level 12% to 26% Treatment 3: high Type-C crystal level \>26%
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 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. Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin) 5. 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 (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing) 6. 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 (e.g., 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. 7. Male participants must have had a successful vasectomy (confirmed azoospermia) or they and their female partners must meet the criteria above (i.e., 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. 8. Provide written informed consent
Exclusion criteria
1. Clinically significant illness that requires medical treatment within 8 weeks of Screening or a clinically significant infection that requires medical treatment within 4 weeks of dosing 2. Evidence of disease that may influence the outcome of the study within 4 weeks prior to dosing, e.g., psychiatric disorders and disorders of the gastrointestinal 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 GI surgery that may affect pharmacokinetic profiles of lenvatinib e.g., hepatectomy, nephrotomy, digestive organ resection known at Screening or Baseline 4. Any clinically abnormal symptom or organ impairment found by medical history, physical examinations, vital signs, ECG findings, or laboratory test results that require medical treatment at Screening or Baseline 5. Blood pressure measurements of greater than 150/90 mm Hg. Confirmation should be obtained by performing three measurements (at least 5 minutes apart) to yield a mean value. Participants may be enrolled if they are on a stable dose of a single antihypertensive drug at least 30 days prior to the first dose of study drug and do not intend to change the dose or drug during the study. 6. A prolonged QTcF interval (QTcF greater than 450 ms) demonstrated on ECG at Screening or Baseline 7. Known history of clinically significant drug allergy at Screening or Baseline 8. Known history of food allergies or presently experiencing significant seasonal or perennial allergy at Screening or Baseline or with a known history of sensitivity to any of the components of the test products 9. Known to be human immunodeficiency virus 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 a positive urine drug test at Screening or Baseline 12. Intake of grapefruit or grapefruit-containing beverages or food within 72 hours prior to dosing 13. Intake of medications known to be strong inhibitors or inducers of CYP450 3A4 metabolizing enzymes within 2 weeks prior to dosing 14. Currently enrolled in another clinical trial or used any investigational drug or device within 30 days preceding informed consent 15. Receipt of blood products within 4 weeks, or donation of blood within 8 weeks, or donation of plasma within 1 week of dosing 16. Engagement in strenuous exercise within 2 weeks prior to check-in (e.g., marathon runners, weight lifters) 17. Any condition that would make the participant, in the opinion of the investigator or sponsor unsuitable for the study or not likely to complete the study for any reason
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve From Zero Time (Predose) to Time of Last Quantifiable Concentration (AUC(0-t)) | Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose | Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for \>24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) methodology using a previously validated assay. The lower limit of quantitation (LLOQ) for the assay was 0.25 ng/mL. AUC(0-t) was calculated by the linear-up log-down trapezoidal method. No concentration estimates were provided for missing sample values. Any sample with a missing value was treated as if the sample had not been scheduled for collection. |
| Area Under the Concentration-Time Curve From Zero Time (Predose) Extrapolated to Infinite Time (AUC(0-inf)) | Periods 1, 2, and 3; 0 (Predose), 2, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. | Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for \>24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL. AUC(0-t) was calculated by the linear-up log-down trapezoidal method. AUC(0-inf) was calculate as follows; (AUC(0-inf)) = (AUC(0-t)) + (Ct/Kel), where Ct is the last measurable drug concentration and Kel is the elimination rate constant. The apparent first-order Kel was estimated, when possible, from the slope of the regression line for the terminal ln-linear concentration-time values. |
| Area Under the Concentration-Time Curve From Zero Time (Predose) to 24 Hours (AUC(0-24)) | Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, and 24 hours postdose | Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for \>24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Terminal Elimination Phase Half-life (t1/2) | Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose | Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for \>24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL. |
| Area Under the Concentration-Time Curve From Zero Time (Predose) to 72 Hours (AUC(0-72)) | Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, and 72 hours postdose | Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for \>24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL. |
| Number of Participants With Non-Serious Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability of Lenvatinib | From date of first dose up to 30 days after the last dose of study treatment, up to approximately 2 months | Safety assessments consisted of monitoring and recording all adverse events (AEs) (serious and non-serious); regular monitoring of hematology, blood chemistry and urine values; periodic measurement of vital signs and electrocardiograms, performance of physical examinations. A TEAE was defined as an AE that emerges during treatment, having been absent at pretreatment (Baseline), or reemerges during treatment, having been present at pretreatment but stopped before treatment, or worsens in severity during treatment relative to the pretreatment state, when the AE is continuous. TEAEs considered by the investigator to be possibly or probably related to study drug, or TEAEs with missing causality, were included. |
| Maximum Observed Concentration (Cmax) of Lenvatinib in Plasma | Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose | Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for \>24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL. |
| Time to Cmax (Tmax) for Lenvatinib | Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose | Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for \>24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sequence A The Randomization Phase consisted of three 6-day long Treatment Periods with each Period separated by a 1-day long Baseline. Sixty participants were evenly randomized to one of 6 possible treatment sequences (A, B, C, D, E, or F). Participants in Sequence A were administered lenvatinib with 240 mL of water in the following sequence; Treatment 1 (low Crystal form Type-C level \<4%), Treatment 2 (reference\* Crystal form Type-C level 15%, \*reference range determined from clinical batches), and Treatment 3 (high Crystal form Type-C level 38%) on the morning of Days 1, 8, and 15 following an overnight fast of at least 10 hours. No food was allowed for at least 4 hours postdose. Water was allowed ad libitum except for the period beginning 1 hour before and lasting until 1 hour after treatment. Treatments were administered at the same time on the 3 mornings. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals. | 10 |
| Sequence B The Randomization Phase consisted of three 6-day long Treatment Periods with each Period separated by a 1-day long Baseline. Sixty participants were evenly randomized to one of 6 possible treatment sequences (A, B, C, D, E, or F). Participants in Sequence B were administered lenvatinib with 240 mL of water in the following sequence; Treatment 2 (reference\* Crystal form Type-C level 15%, \*reference range determined from clinical batches), Treatment 3 (high Crystal form Type-C level 38%), and Treatment 1 (low Crystal form Type-C level \<4%), on the morning of Days 1, 8, and 15 following an overnight fast of at least 10 hours. No food was allowed for at least 4 hours postdose. Water was allowed ad libitum except for the period beginning 1 hour before and lasting until 1 hour after treatment. Treatments were administered at the same time on the 3 mornings. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals. | 10 |
| Sequence C The Randomization Phase consisted of three 6-day long Treatment Periods with each Period separated by a 1-day long Baseline. Sixty participants were evenly randomized to one of 6 possible treatment sequences (A, B, C, D, E, or F). Participants in Sequence C were administered lenvatinib with 240 mL of water in the following sequence; Treatment 3 (high Crystal form Type-C level 38%), Treatment 1 (low Crystal form Type-C level \<4%), and Treatment 2 (reference\* Crystal form Type-C level 15%, \*reference range determined from clinical batches), on the morning of Days 1, 8, and 15 following an overnight fast of at least 10 hours. No food was allowed for at least 4 hours postdose. Water was allowed ad libitum except for the period beginning 1 hour before and lasting until 1 hour after treatment. Treatments were administered at the same time on the 3 mornings. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals. | 10 |
| Sequence D The Randomization Phase consisted of three 6-day long Treatment Periods with each Period separated by a 1-day long Baseline. Sixty participants were evenly randomized to one of 6 possible treatment sequences (A, B, C, D, E, or F). Participants in Sequence D were administered lenvatinib with 240 mL of water in the following sequence; Treatment 3 (high Crystal form Type-C level 38%), Treatment 2 (reference\* Crystal form Type-C level 15%, \*reference range determined from clinical batches), and Treatment 1 (low Crystal form Type-C level \<4%), on the morning of Days 1, 8, and 15 following an overnight fast of at least 10 hours. No food was allowed for at least 4 hours postdose. Water was allowed ad libitum except for the period beginning 1 hour before and lasting until 1 hour after treatment. Treatments were administered at the same time on the 3 mornings. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals. | 10 |
| Sequence E The Randomization Phase consisted of three 6-day long Treatment Periods with each Period separated by a 1-day long Baseline. Sixty participants were evenly randomized to one of 6 possible treatment sequences (A, B, C, D, E, or F). Participants in Sequence E were administered lenvatinib with 240 mL of water in the following sequence; Treatment 1 (low Crystal form Type-C level \<4%), Treatment 3 (high Crystal form Type-C level 38%), and Treatment 2 (reference\* Crystal form Type-C level 15%, \*reference range determined from clinical batches), on the morning of Days 1, 8, and 15 following an overnight fast of at least 10 hours. No food was allowed for at least 4 hours postdose. Water was allowed ad libitum except for the period beginning 1 hour before and lasting until 1 hour after treatment. Treatments were administered at the same time on the 3 mornings. On dosing days, all participants observed identical schedules with respect to fasting before dosing and timing of postdose meals. | 10 |
| Sequence F The Randomization Phase consisted of three 6-day long Treatment Periods with each Period separated by a 1-day long Baseline. Sixty participants were evenly randomized to one of 6 possible treatment sequences (A, B, C, D, E, or F). Participants in Sequence F were administered lenvatinib with 240 mL of water in the following sequence; Treatment 2 (reference\* Crystal form Type-C level 15%, \*reference range determined from clinical batches), Treatment 1 (low Crystal form Type-C level \<4%), and Treatment 3 (high Crystal form Type-C level 38%), on the morning of Days 1, 8, and 15 following an overnight fast of at least 10 hours. No food was allowed for at least 4 hours postdose. Water was allowed ad libitum except for the period beginning 1 hour before and lasting until 1 hour after treatment. Treatments were administered at the same time on the 3 mornings. 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 |
|---|---|---|---|---|---|---|---|
| Intervention Period 1 | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 |
| Intervention Period 3 | consumption of restricted item | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Sequence A | Sequence B | Sequence C | Sequence D | Sequence E | Sequence F | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 45.1 Years STANDARD_DEVIATION 9.55 | 45.1 Years STANDARD_DEVIATION 10.72 | 36.3 Years STANDARD_DEVIATION 13.41 | 40.4 Years STANDARD_DEVIATION 10.8 | 31.7 Years STANDARD_DEVIATION 10.36 | 37.8 Years STANDARD_DEVIATION 12.06 | 39.4 Years STANDARD_DEVIATION 11.77 |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 15 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 59 | 0 / 59 | 0 / 59 |
| other Total, other adverse events | 14 / 59 | 14 / 59 | 12 / 59 |
| serious Total, serious adverse events | 1 / 59 | 0 / 59 | 0 / 59 |
Outcome results
Primary
Area Under the Concentration-Time Curve From Zero Time (Predose) Extrapolated to Infinite Time (AUC(0-inf))
Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for \>24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL. AUC(0-t) was calculated by the linear-up log-down trapezoidal method. AUC(0-inf) was calculate as follows; (AUC(0-inf)) = (AUC(0-t)) + (Ct/Kel), where Ct is the last measurable drug concentration and Kel is the elimination rate constant. The apparent first-order Kel was estimated, when possible, from the slope of the regression line for the terminal ln-linear concentration-time values.
Time frame: Periods 1, 2, and 3; 0 (Predose), 2, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose.
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment 1: Low Crystal Form | Area Under the Concentration-Time Curve From Zero Time (Predose) Extrapolated to Infinite Time (AUC(0-inf)) | 1030 ng·hr/mL | Geometric Coefficient of Variation 40 |
| Treatment 2: Reference Crystal Form | Area Under the Concentration-Time Curve From Zero Time (Predose) Extrapolated to Infinite Time (AUC(0-inf)) | 1020 ng·hr/mL | Geometric Coefficient of Variation 36.9 |
| Treatment 3: High Crystal Form | Area Under the Concentration-Time Curve From Zero Time (Predose) Extrapolated to Infinite Time (AUC(0-inf)) | 991 ng·hr/mL | Geometric Coefficient of Variation 39 |
Comparison: The effect of crystalline polymorph forms in the drug product on the PK parameters of lenvatinib was estimated using a mixed linear model of logarithmically transformed values of the primary PK parameters with fixed effects for treatment, period, and sequence and a random effect for participant within sequence.p-value: 0.812190% CI: [95.31, 106.61]Mixed Models Analysis
Comparison: The effect of crystalline polymorph forms in the drug product on the PK parameters of lenvatinib was estimated using a mixed linear model of logarithmically transformed values of the primary PK parameters with fixed effects for treatment, period, and sequence and a random effect for participant within sequence.p-value: 0.16390% CI: [92.53, 100.65]Mixed Models Analysis
Primary
Area Under the Concentration-Time Curve From Zero Time (Predose) to 24 Hours (AUC(0-24))
Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for \>24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL.
Time frame: Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, and 24 hours postdose
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment 1: Low Crystal Form | Area Under the Concentration-Time Curve From Zero Time (Predose) to 24 Hours (AUC(0-24)) | 791 ng·hr/mL | Geometric Coefficient of Variation 47.4 |
| Treatment 2: Reference Crystal Form | Area Under the Concentration-Time Curve From Zero Time (Predose) to 24 Hours (AUC(0-24)) | 792 ng·hr/mL | Geometric Coefficient of Variation 39.2 |
| Treatment 3: High Crystal Form | Area Under the Concentration-Time Curve From Zero Time (Predose) to 24 Hours (AUC(0-24)) | 740 ng·hr/mL | Geometric Coefficient of Variation 43.5 |
Comparison: The effect of crystalline polymorph forms in the drug product on the PK parameters of lenvatinib was estimated using a mixed linear model of logarithmically transformed values of the primary PK parameters with fixed effects for treatment, period, and sequence and a random effect for participant within sequence.p-value: 0.942790% CI: [92.45, 107.47]Mixed Models Analysis
Comparison: The effect of crystalline polymorph forms in the drug product on the PK parameters of lenvatinib was estimated using a mixed linear model of logarithmically transformed values of the primary PK parameters with fixed effects for treatment, period, and sequence and a random effect for participant within sequence.p-value: 0.040390% CI: [88.63, 98.64]Mixed Models Analysis
Primary
Area Under the Plasma Concentration-Time Curve From Zero Time (Predose) to Time of Last Quantifiable Concentration (AUC(0-t))
Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for \>24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) methodology using a previously validated assay. The lower limit of quantitation (LLOQ) for the assay was 0.25 ng/mL. AUC(0-t) was calculated by the linear-up log-down trapezoidal method. No concentration estimates were provided for missing sample values. Any sample with a missing value was treated as if the sample had not been scheduled for collection.
Time frame: Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose
Population: Pharmacokinetic (PK) analysis set included participants who had sufficient PK data to derive at least one PK parameter. Participants with a predose concentration \>5% Cmax and participants who experienced emesis at or before two times median tmax were excluded from the data analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment 1: Low Crystal Form | Area Under the Plasma Concentration-Time Curve From Zero Time (Predose) to Time of Last Quantifiable Concentration (AUC(0-t)) | 1010 ng·hr/mL | Geometric Coefficient of Variation 40.4 |
| Treatment 2: Reference Crystal Form | Area Under the Plasma Concentration-Time Curve From Zero Time (Predose) to Time of Last Quantifiable Concentration (AUC(0-t)) | 1010 ng·hr/mL | Geometric Coefficient of Variation 36.9 |
| Treatment 3: High Crystal Form | Area Under the Plasma Concentration-Time Curve From Zero Time (Predose) to Time of Last Quantifiable Concentration (AUC(0-t)) | 965 ng·hr/mL | Geometric Coefficient of Variation 39.3 |
Comparison: The effect of crystalline polymorph forms in the drug product on the PK parameters of lenvatinib was estimated using a mixed linear model of logarithmically transformed values of the primary PK parameters with fixed effects for treatment, period, and sequence and a random effect for participant within sequence.p-value: 0.882690% CI: [94.84, 106.53]Mixed Models Analysis
Comparison: The effect of crystalline polymorph forms in the drug product on the PK parameters of lenvatinib was estimated using a mixed linear model of logarithmically transformed values of the primary PK parameters with fixed effects for treatment, period, and sequence and a random effect for participant within sequence.p-value: 0.109590% CI: [92.11, 100.12]Mixed Models Analysis
Secondary
Area Under the Concentration-Time Curve From Zero Time (Predose) to 72 Hours (AUC(0-72))
Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for \>24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL.
Time frame: Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, and 72 hours postdose
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment 1: Low Crystal Form | Area Under the Concentration-Time Curve From Zero Time (Predose) to 72 Hours (AUC(0-72)) | 975 ng·hr/mL | Geometric Coefficient of Variation 40.5 |
| Treatment 2: Reference Crystal Form | Area Under the Concentration-Time Curve From Zero Time (Predose) to 72 Hours (AUC(0-72)) | 971 ng·hr/mL | Geometric Coefficient of Variation 36.7 |
| Treatment 3: High Crystal Form | Area Under the Concentration-Time Curve From Zero Time (Predose) to 72 Hours (AUC(0-72)) | 923 ng·hr/mL | Geometric Coefficient of Variation 39.4 |
Comparison: The effect of crystalline polymorph forms in the drug product on the PK parameters of lenvatinib was estimated using a mixed linear model of logarithmically transformed values of the primary PK parameters with fixed effects for treatment, period, and sequence and a random effect for participant within sequence.p-value: 0.937390% CI: [94.37, 106.58]Mixed Models Analysis
Comparison: The effect of crystalline polymorph forms in the drug product on the PK parameters of lenvatinib was estimated using a mixed linear model of logarithmically transformed values of the primary PK parameters with fixed effects for treatment, period, and sequence and a random effect for participant within sequence.p-value: 0.068290% CI: [91.03, 99.5]Mixed Models Analysis
Secondary
Maximum Observed Concentration (Cmax) of Lenvatinib in Plasma
Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for \>24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL.
Time frame: Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment 1: Low Crystal Form | Maximum Observed Concentration (Cmax) of Lenvatinib in Plasma | 96.0 ng/mL | Geometric Coefficient of Variation 64 |
| Treatment 2: Reference Crystal Form | Maximum Observed Concentration (Cmax) of Lenvatinib in Plasma | 97.1 ng/mL | Geometric Coefficient of Variation 49.2 |
| Treatment 3: High Crystal Form | Maximum Observed Concentration (Cmax) of Lenvatinib in Plasma | 88.0 ng/mL | Geometric Coefficient of Variation 57.7 |
Comparison: The effect of crystalline polymorph forms in the drug product on the PK parameters of lenvatinib was estimated using a mixed linear model of logarithmically transformed values of the primary PK parameters with fixed effects for treatment, period, and sequence and a random effect for participant within sequence.p-value: 0.844890% CI: [88.57, 110.06]Mixed Models Analysis
Comparison: The effect of crystalline polymorph forms in the drug product on the PK parameters of lenvatinib was estimated using a mixed linear model of logarithmically transformed values of the primary PK parameters with fixed effects for treatment, period, and sequence and a random effect for participant within sequence.p-value: 0.049890% CI: [83.51, 98.38]Mixed Models Analysis
Secondary
Number of Participants With Non-Serious Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability of Lenvatinib
Safety assessments consisted of monitoring and recording all adverse events (AEs) (serious and non-serious); regular monitoring of hematology, blood chemistry and urine values; periodic measurement of vital signs and electrocardiograms, performance of physical examinations. A TEAE was defined as an AE that emerges during treatment, having been absent at pretreatment (Baseline), or reemerges during treatment, having been present at pretreatment but stopped before treatment, or worsens in severity during treatment relative to the pretreatment state, when the AE is continuous. TEAEs considered by the investigator to be possibly or probably related to study drug, or TEAEs with missing causality, were included.
Time frame: From date of first dose up to 30 days after the last dose of study treatment, up to approximately 2 months
Population: Safety analysis set (SAS) included the group of participants who received at least one dose of study drug and had at least one postdose safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment 1: Low Crystal Form | Number of Participants With Non-Serious Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability of Lenvatinib | TEAEs | 23.7 Percentage of participants |
| Treatment 1: Low Crystal Form | Number of Participants With Non-Serious Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability of Lenvatinib | Treatment-related TEAEs | 18.6 Percentage of participants |
| Treatment 1: Low Crystal Form | Number of Participants With Non-Serious Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability of Lenvatinib | Severe TEAEs | 1.69 Percentage of participants |
| Treatment 1: Low Crystal Form | Number of Participants With Non-Serious Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability of Lenvatinib | Serious TEAEs | 1.69 Percentage of participants |
| Treatment 2: Reference Crystal Form | Number of Participants With Non-Serious Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability of Lenvatinib | Serious TEAEs | 0 Percentage of participants |
| Treatment 2: Reference Crystal Form | Number of Participants With Non-Serious Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability of Lenvatinib | TEAEs | 23.7 Percentage of participants |
| Treatment 2: Reference Crystal Form | Number of Participants With Non-Serious Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability of Lenvatinib | Severe TEAEs | 0 Percentage of participants |
| Treatment 2: Reference Crystal Form | Number of Participants With Non-Serious Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability of Lenvatinib | Treatment-related TEAEs | 15.2 Percentage of participants |
| Treatment 3: High Crystal Form | Number of Participants With Non-Serious Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability of Lenvatinib | Serious TEAEs | 0 Percentage of participants |
| Treatment 3: High Crystal Form | Number of Participants With Non-Serious Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability of Lenvatinib | Treatment-related TEAEs | 16.9 Percentage of participants |
| Treatment 3: High Crystal Form | Number of Participants With Non-Serious Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability of Lenvatinib | Severe TEAEs | 0 Percentage of participants |
| Treatment 3: High Crystal Form | Number of Participants With Non-Serious Treatment-Emergent Adverse Events (TEAEs) and Serious Treatment-Emergent Adverse Events as a Measure of Safety and Tolerability of Lenvatinib | TEAEs | 20.3 Percentage of participants |
Secondary
Terminal Elimination Phase Half-life (t1/2)
Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for \>24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL.
Time frame: Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment 1: Low Crystal Form | Terminal Elimination Phase Half-life (t1/2) | 24.1 Hours | Standard Deviation 6.88 |
| Treatment 2: Reference Crystal Form | Terminal Elimination Phase Half-life (t1/2) | 24.2 Hours | Standard Deviation 6.23 |
| Treatment 3: High Crystal Form | Terminal Elimination Phase Half-life (t1/2) | 23.5 Hours | Standard Deviation 6.61 |
Secondary
Time to Cmax (Tmax) for Lenvatinib
Blood samples (6 mL each) were collected at the following time points for each Period: 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose. The window for 0 to 12 hours was +/-2 minutes, for 24 hours was +/-5 minutes and for \>24 hours was equal to +/-15 to 60 minutes. Plasma concentrations of lenvatinib were quantified by LC-MS/MS methodology using a previously validated assay. The LLOQ for the assay was 0.25 ng/mL.
Time frame: Periods 1, 2, and 3; 0 (Predose), 1, 2, 3, 4, 8, 12, 24, 48, 72, 96, and 120 hours postdose
Population: PK analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment 1: Low Crystal Form | Time to Cmax (Tmax) for Lenvatinib | 3.000 Hours |
| Treatment 2: Reference Crystal Form | Time to Cmax (Tmax) for Lenvatinib | 3.000 Hours |
| Treatment 3: High Crystal Form | Time to Cmax (Tmax) for Lenvatinib | 3.000 Hours |