This is a Phase I, open label, sequential, single ascending dose (SAD) study to evaluate the pharmacokinetic (PK), safety, and tolerability of Letrozole LEBE in healthy post-menopausal women.
The study consists of 1 Screening Period and 2 treatment periods. Evaluation of eligibility and allocation of subject number to the volunteers will be performed after Screening. It is planned that subjects will be enrolled in three groups of approximately 30 subjects in each group (Groups 1 to 3), in order to ensure 15 completed subjects per group in Treatment Period 1 and Treatment Period 2. In Treatment Period 1, each subject will sequentially receive 1 dose daily of oral Femara (2.5 mg) over a period of 14 days followed by a single intramuscular (IM) dose of Letrozole LEBE (after a washout period) in Treatment Period 2. Ascending doses of Letrozole LEBE will be given to Groups 1, 2 and 3. Safety and tolerability will be assessed in all groups by the incidence and severity of Adverse Events (AEs) and Serious AEs (SAEs), concomitant medication use, vital sign assessments, clinical laboratory evaluations, 12 lead ECGs, physical examination, and body weight/BMI. The end of the clinical trial will be the last visit of the last subject at Day 197 of Treatment Period 2 or any additionally required 4-weeks safety follow up visits, when plasma levels of letrozole are detectable, whichever occurs later. Those remaining subjects with detectable plasma levels of letrozole could be followed every 4 weeks. The sample size was estimated based on a minimum number necessary to obtain a preliminary assessment regarding the drug's PK and safety profile over the planned dose range. No formal sample size calculation was made for this study.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
90
14 oral doses of Femara 2.5 mg/daily + 28-days (at least) washout period + single IM injection of Letrozole LEBE 75 mg
14 oral doses of Femara 2.5 mg/daily + 28-days (at least) washout period + single IM injection of Letrozole LEBE 150 mg
14 oral doses of Femara 2.5 mg/daily + 28-days (at least) washout period + single IM injection of Letrozole LEBE 225mg
Investigational Site number CZ-01
Prague, Czechia
λz
Terminal phase elimination rate constant
Time frame: Following single IM administration of Letrozole LEBE (Treatment Period 2, Day 1) until Day 197
Cmax
Maximum observed plasma concentration after Letrozole LEBE administration
Time frame: Following single IM administration of Letrozole LEBE (Treatment Period 2, Day 1) until Day 197
Clast
Last observed plasma concentration after Letrozole LEBE administration
Time frame: Following single IM administration of Letrozole LEBE (Treatment Period 2, Day 1) until Day 197
tmax
Time to maximum observed concentration
Time frame: Following single IM administration of Letrozole LEBE (Treatment Period 2, Day 1) until Day 197
tlag
Lag time before observation of quantifiable concentrations in plasma.
Time frame: Following single IM administration of Letrozole LEBE (Treatment Period 2, Day 1) until Day 197
t1/2
Terminal elimination half life.
Time frame: Following single IM administration of Letrozole LEBE (Treatment Period 2, Day 1) until Day 197
AUC∞
Area under the concentration time curve from time zero extrapolated to infinity.
Time frame: Following single IM administration of Letrozole LEBE (Treatment Period 2, Day 1) until Day 197
AUClast
Area under the concentration time curve from time zero up to the last quantifiable concentration.
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Time frame: Following single IM administration of Letrozole LEBE (Treatment Period 2, Day 1) until Day 197
E1
Estrone
Time frame: Following single IM administration of Letrozole LEBE (Treatment Period 2, Day 1) until Day 197
SE1
Sulfate estrone
Time frame: Following single IM administration of Letrozole LEBE (Treatment Period 2, Day 1) until Day 197
E2
Estradiol
Time frame: Following single IM administration of Letrozole LEBE (Treatment Period 2, Day 1) until Day 197
λz
Terminal phase elimination rate constant.
Time frame: Following multiple oral administration of Femara (Treatment Period 1, Day 14)
Cav
Average plasma concentration over a dosing interval.
Time frame: Following multiple oral administration of Femara (Treatment Period 1, Day 14)
Cmin, ss
Minimum observed plasma concentration at steady-state.
Time frame: Following multiple oral administration of Femara (Treatment Period 1, Day 14)
Cmax,ss
Maximum observed plasma concentration at steady-state
Time frame: Following multiple oral administration of Femara (Treatment Period 1, Day 14)
tmax
Time to maximum observed concentration.
Time frame: Following multiple oral administration of Femara (Treatment Period 1, Day 14)
t1/2
Terminal elimination half-life.
Time frame: Following multiple oral administration of Femara (Treatment Period 1, Day 14)
AUCτ
Area under the concentration-time curve over a dosing interval.
Time frame: Following multiple oral administration of Femara (Treatment Period 1, Day 14)