Disease Severity, Renal Impairment
Conditions
Keywords
renal impairment, disease severity
Brief summary
The purpose of this multicenter, open-label, non-randomized, single, oral dose, sequential-cohort study was to determine pharmacokinetics and safety of lenvatinib (24 mg) administered to healthy subjects and to subjects with renal impairment.
Detailed description
This is a multicenter, open-label, non-randomized, single-dose, sequential-cohort trial in subjects with renal impairment and healthy subjects. The study consists of two phases: A Pretreatment Phase and a Treatment Phase. The two periods in the Pretreatment Phase are: (1) the Screening Period (lasting up to 29 days), and (2) the Baseline Period (one day). The Treatment Period of the Treatment Phase lasts 8 days. The study will enroll a sufficient number of subjects so that 24 to 26 subjects complete the study. This will include six subjects with mild renal impairment (Group 1), six subjects with moderate renal impairment (Group 2), four to six subjects with severe renal impairment (Group 3) and eight subjects with normal renal function (Group 4). Subjects determined to be eligible for the protocol will receive a single 24-mg oral dose of E7080 on Day 1. Subjects will be discharged from clinical site on Day 8.
Interventions
DRUGLenvatinib
Lenvatinib will be taken as a single dose of 24 mg consisting of 2 x 10 mg and 1 x 4 mg capsules. Treatment will be administered orally with 240 mL of water following a 10-hour overnight fast.
Sponsors
Eisai Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
Yes
Inclusion criteria
All subjects should meet all of the following criteria to be included in this study: 1. Male or female subjects, ages 18 to 79, inclusive, at the time of informed consent 2. BMI, 18 to 40 kg/m2, inclusive, at Screening 3. Nonsmokers and smokers who smoke no more than 10 cigarettes per day 4. All females must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human chorionic gonadotropin \[B-hCG\] at the Screening Visit or within 72 hours before the first dose of study drug). Females of child-bearing potential, if not practicing total abstinence or having a vasectomised partner with confirmed azoospermia, must agree to use two highly effective methods of contraception: e.g., 1) an intrauterine device (IUD) or intrauterine system (IUS); 2) a barrier method such as a condom or occlusive cup (diaphragm or cervical/vault caps) plus spermicide (foam, gel, cream, etc.); 3) oral, injected, or implanted hormonal contraceptives throughout the entire study period and for 30 days after study drug discontinuation. Use of a double-barrier method (i.e., use at the same time of a condom plus occlusive cup \[diaphragm or cervical/vault caps\] plus spermicide \[foam, gel, cream, etc.\]) is accepted as two highly effective methods of contraception. The only subjects who will be exempt from this requirement are postmenopausal women (defined as women who have been amenorrheic for at least 12 consecutive months, in the appropriate age group, without other known or suspected primary cause) or subjects who have been sterilized surgically or who are otherwise proven sterile (i.e., bilateral tubal ligation with surgery at least 1 month prior to dosing, total hysterectomy, or bilateral oophorectomy with surgery at least 1 month prior to dosing). All women who are of reproductive potential and who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks prior to dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation. 5. Male subjects who are partners of women of childbearing potential must use a condom plus spermicide and their female partners if of childbearing potential must use a highly effective method of contraception (see methods described in Inclusion Criterion No. 4) beginning at least one menstrual cycle prior to starting study drug, throughout the entire study period, and for 30 days after the last dose of study drug, unless the male subjects are totally sexually abstinent or have undergone a successful vasectomy with confirmed azoospermia or unless the female partners have been sterilized surgically or are otherwise proven sterile (see Inclusion Criterion No.4). 6. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol. For healthy subjects with normal renal function the following key inclusion criterion will also apply: 1\. Creatinine clearance greater than or equal to 90 mL/min. For subjects with renal impairment, the following key inclusion criteria will also apply: 1. Subjects must have a diagnosis of renal impairment that has been stable, without any change in disease status, for 60 days prior to study screening, as determined by the investigator. 2. Mild (creatinine clearance, 60-89 mL/min), moderate (creatinine clearance, 30-59 mL/min), or severe (creatinine clearance, 15-29 mL/min) renal impairment 3. Other than renal impairment, subjects must have no history of clinically relevant disease or condition (e.g., significant cardiac or hepatic dysfunction, diseases of the gastrointestinal tract or conditions which may impact drug absorption), as determined by the investigator. 4. Subjects with a history of Type I or Type II diabetes are permissible, providing that, in the opinion of the investigator, they have stable disease. Subjects receiving insulin therapy are permissible provided that they have been on a stable treatment for at least 2 weeks prior to study enrollment and continuing through the study. 5. QT interval corrected for heart rate (QTc) calculated by Fridericia's formula (QTcF) interval lesser than or equal to 500 msec at Screening and Baseline. 6. Subjects may be enrolled with joint approval of the principal investigator (PI) and medical monitor based on subject history and stability of the renal impairment.
Exclusion criteria
Subjects who meet any of the following criteria will be excluded from this study: All Subjects: 1. Use of any new medication, including multivitamins, or investigational drug within 14 days prior to the drug administration, or within five times the elimination half-life, whichever is longest, except combined oral contraceptives and occasional use of paracetamol or ibuprofen within 14 days and any local anesthetic within 3 days before study drug administration. Current over-the-counter (OTC) drugs and prescription medication use is permitted, but must be stable and consistent for at least 14 days prior to Screening and throughout the study treatment period. 2. Positive HIV screening test 3. Presence of acute, active liver disease or acute liver injury as indicated by (1) an abnormal liver function test, or (2) clinical or laboratory signs of acute, active hepatitis A, B, or C 4. Systolic blood pressure greater than or equal to 160 mm Hg and/or diastolic blood pressure greater than or equal to 100 mm Hg for healthy subjects and subjects with mild renal impairment; systolic blood pressure greater than or equal to 180 mm Hg and/or diastolic blood pressure greater than or equal to 110 mm Hg for subjects with moderate and severe renal impairment. Readings are to be confirmed by repeat determinations one hour after the first measurement. Healthy Subjects: In addition to the Key
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Pharmacokinetics of lenvatinib: Cmax | Day 1 to Day 8 |
| Pharmacokinetics of lenvatinib: AUC(0-inf) | Day 1 to Day 8 |
| Pharmacokinetics of lenvatinib: AUC(0-t) | Day 1 to Day 8 |
Secondary
| Measure | Time frame |
|---|---|
| Safety as Measured by Laboratory Values | Screening, Baseline and Treatment period (Day 1 to Day 8) |
| Safety as Measured by vital signs | Screening, Baseline and Treatment period (Day 1 to Day 8) |
| Safety as Measured by Outcome of all Adverse Events (AEs) | Screening, Baseline and Treatment period (Day 1 to Day 8) |
| Safety as Measured by performance of physical examinations. | Screening, Baseline and Treatment period (Day 1 to Day 8) |
| Safety as Measured by ECGs | Screening, Baseline and Treatment period (Day 1 to Day 8) |
| Safety as Measured by Outcome of treatment-emergent AEs (TEAEs) | Screening, Baseline and Treatment period (Day 1 to Day 8) |
| Safety as Measured by Outcome of serious adverse events (SAEs) | Screening, Baseline and Treatment period (Day 1 to Day 8) |
Countries
United States
Outcome results
None listed