Crossover Study to Evaluate the Relative Bioavailability and Palatability of a Lenvatinib Suspension Compared to the Capsule Formulation in Adult Healthy Volunteers

Healthy Volunteers Clinical Trial

Official title:

A Randomized Three-Arm, Single-dose, Two-period Crossover Study to Evaluate the Relative Bioavailability and Palatability of a Lenvatinib Suspension Compared to the Capsule Formulation in Adult Healthy Volunteers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02792829
• Other study ID #: E7080-A001-009
• Status: Completed
• Phase: Phase 1
• Start date: August 2014
• Est. completion date: August 2014

Study information

• Verified date: March 2018
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: August 2014
• Est. primary completion date: August 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Healthy Volunteers

Intervention

Drug:
• Lenvatinib
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.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Eisai Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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).	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)
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.	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)
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.	Treatment Period 1: Predose up to 24 hours post dose
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.	Treatment Period 1: Predose up to 72 hours postdose
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.	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)
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).	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)
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).	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)
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.	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)
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.	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)
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.	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)
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.	From date of first dose of study treatment to date of last dose of study treatment, up to approximately 2 months 10 days
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).	Treatment Period 1, Day 1 (Visit 2); Treatment Period 2, Day 8 (Visit 8)