This study evaluates how once daily enzalutamide affects the metabolism of caffeine and dextromethorphan in men with prostate cancer by measuring concentrations of these drugs and their metabolites in plasma.
This is an open-label, fixed-sequence, crossover drug-drug interaction study in subjects with prostate cancer. Screening takes place between Day -28 and Day -7, and subjects are admitted to the clinic on Day -1 where they remain until Day 4. On Day 1, they receive a single oral cocktail containing caffeine and dextromethorphan plus a dose of enzalutamide placebo in order to assess possible effects of excipients of the enzalutamide formulation. On Days 1 to 3 blood samples for pharmacokinetic (PK) assessment are collected. From Days 4 to 54, (or Day 55 if the subject rolls over into the extension study) the subjects take a daily oral dose of enzalutamide. On Day 28, the subjects return to the clinic where a plasma sample is taken to determine enzalutamide PK exposure. From Days 52 to 55 they are re-admitted to the clinic where a plasma sample is collected on Day 52 for enzalutamide PK exposure.On Day 53, subjects receive a single oral cocktail of caffeine and dextromethorphan concomitantly with enzalutamide. PK samples are collected from Days 53 to 55. From Day 55 onwards, subjects experiencing clinical benefit may roll over into an extension study. Only subjects who enroll into the extension study continue to receive enzalutamide otherwise daily dosing with enzalutamide is discontinued on Day 54. An End of Study Visit (ESV) takes place approximately 30 days (±7 days) after the last dose of enzalutamide.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
12
Arensia
Chisinau, Moldova
PK measured by Pharmacokinetic parameter Maximum concentration (Cmax)
For the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.
Time frame: Day 1 and Day 53 (28 times)
PK measured by Pharmacokinetic parameter Area under the curve (AUC) from the time of dosing to the last measurable concentration (AUC0-t)
For the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.
Time frame: Day 1 and Day 53 (28 times)
PK measured by PK parameter area under the curve (AUC) from time 0 extrapolated to infinity (AUC0-inf)
For the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.
Time frame: Day 1 and Day 53 (28 times)
PK measured by PK parameters tmax, terminal elimination half-life (t1/2), apparent total systemic clearance after oral dosing (CL/F), apparent volume of distribution during terminal elimination phase (Vz/F) and extrapolated AUC (%AUC)
Tmax is time to maximum concentration. These PK parameters will be measured for the probe substrates (caffeine and dextromethorphan) in combination with enzalutamide PTM and in combination with enzalutamide.
Time frame: Day 1 and Day 53 (28 times)
PK measured by PK parameters Cmax, AUC0-t, AUC0-inf, %AUC, tmax and t1/2
For 1,7-dimethylxanthine (metabolite caffeine), dextrorphan (metabolite dextromethorphan).
Time frame: Day 1 and Day 53 (28 times)
PK measured by PK parameters Cmax, trough concentrations (Ctrough) at Days 28, 52, 53, 54 and 55, tmax, AUC during the time interval between consecutive dosing (AUCtau), CL/F (parent only) and peak-to-trough ratio (PTR)
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Oral
For Enzalutamide, N-desmethyl enzalutamide (M2) and sum of enzalutamide + M2.
Time frame: Day 28 (± 1 day), and Days 52 to 55 (15 times)
Safety and tolerability measured by vital signs, adverse events, laboratory assessments and electrocardiogram
Time frame: Screening (Day -28 to Day -7) to ESV (>153 times)