This is a phase 1 open label, 4 treatment, 4 sequence and 4 period crossover study in subjects with solid tumours no longer responding to, or eligible for standard therapies, and for whom there are no additional standard therapies likely to benefit the subject.
The study is an open-label, randomised, 4-period, 4-sequence crossover pharmacokinetic study designed to generate in vivo PK data from tablet variants with different size/geometry and dose, to correlate with their corresponding in vitro dissolution profiles. The duration of each dosing period is 7 days including the washout period. Subjects will be randomised to a treatment sequence, following a balanced Latin Squares design. Twelve subjects who meet inclusion/exclusion criteria and have provided informed consent will be randomly assigned to the treatment sequences: ABCD, BDAC, CADB, or DCBA. On Day 1 of each period, subjects will receive a single dose of either Treatment A, B, C, or D, according to the randomisation schedule. Serial blood samples for determination of olaparib in plasma will be collected for up to 72 hours. Cancer subjects with advanced solid tumours are required for this study, as pre-clinical toxicology data preclude the use of olaparib in healthy volunteers. The olaparib doses chosen will deliver exposure at or below that which has been previously demonstrated to be acceptable and tolerated in cancer subjects.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
18
Olaparib Tablet 25 mg
Olaparib Tablet 100 mg
Olaparib Tablet 150 mg
Research Site
Leuven, Belgium
Research Site
Liège, Belgium
Research Site
Wilrijk, Belgium
%PECmax
Percent prediction error for Cmax
Time frame: 0 to 72 hours
%PEAUC
Percent prediction error for AUC
Time frame: 0 to 72 hours
Maximum plasma concentration (Cmax) obtained directly from the observed concentration versus time data.
Evaluation of the PK parameters for the different Olaparib tablet variants.
Time frame: Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles.
Time to maximum plasma concentration (tmax) obtained directly from the observed concentration versus time data.
Evaluation of the PK parameters for the different Olaparib tablet variants.
Time frame: Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles.
Area under the plasma concentration-time curve from zero to the time of the last measurable concentration (AUC(0-t)) calculated by linear up/log down trapezoidal summation.
Evaluation of the PK parameters for the different Olaparib tablet variants.
Time frame: Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles.
Area under the plasma concentration time curve from zero (pre-dose) extrapolated to infinity (AUC)
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Olaparib Tablet 250 mg
Evaluation of the PK parameters for the different Olaparib tablet variants. calculated by linear up/log down trapezoidal summation and extrapolated to infinity by addition of the last quantifiable concentration divided by the terminal rate constant: AUC(0-t) + Clast/λz.
Time frame: Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles.
Apparent plasma clearance (CL/F).
Evaluation of the PK parameters for the different Olaparib tablet variants.
Time frame: Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles.
Terminal half-life (t½). Visual assessment will be used to identify the terminal linear phase of the concentration-time profile.
Evaluation of the PK parameters for the different Olaparib tablet variants.
Time frame: Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles.
Apparent volume of distribution (Vz/F).
Evaluation of the PK parameters for the different Olaparib tablet variants.
Time frame: Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles.
Terminal rate constant (λz) estimated by log-linear least squares regression of the terminal part of the concentration-time curve.
Evaluation of the PK parameters for the different Olaparib tablet variants.
Time frame: Blood samples will be taken at the following sampling times: Pre-dose, 30 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr (Day 1), 24 hr (Day2), 48 hr (Day 3), and 72 hr (Day 4). After each dosing at each of the 4 treatment cycles.