Improving bio-availability of the expensive oral oncolytic drug abiraterone by food intake

Abiraterone is a selective inhibitor of androgen biosynthesis that potently and
irreversibly blocks CYP17, a crucial enzyme in testosterone and oestrogen
synthesis. A pro-drug of abiraterone, abiraterone acetate (Zytiga®), was
developed to overcome its poor bio-availability and is fully converted to the
active moiety abiraterone. Abiraterone acetate tablets are administered at a
fixed oral dose of 1000mg QD in a fasted state in combination with 10mg
prednisolon daily.
Abiraterone acetate has a low solubility in aqueous media and a low
permeability. The bioavailability of abiraterone acetate is significantly
influenced when ingested with food. Ingesting abiraterone acetate with a low
fat or a high fat meal resulted respectively in a 5- or 10-fold increase in
AUC0-*. The high and low fat FDA meals used in these food effect studies differ
largely from breakfasts taken in everyday life(ca. 800-1000 cal). A continental
breakfast contains 160 to 320 calories of which 25-50% is fat, is more
compatible with a normal lifestyle and therefore easily sustainable in daily
practice. However, the effect of a continental breakfast on the absorption of
abiraterone is unknown yet. Furthermore, increasing healthcare costs are a
growing concern in all developed countries. Therefore effort should be
invested to keep anticancer treatment affordable. A food intervention resulting
in a better absorption and enhanced exposure to abiraterone, can lead to a
reduced dose, which could significantly impact health care costs for a tumor
which is so prevalent as metastatic prostate cancer.

Primary objective:
To determine the equivalent dose of abiraterone when taken with a continental
breakfast compared to 1000 mg in fasted state
Secondary objective:
To evaluate the preference of the patients: intake of abiraterone with or
without food

Patients who use abiraterone are included.
A total of 24-27 patients will be included. Pharmacokinetic (PK) and safety
evaluation will initially be performed in three patients treated with 1000 mg
QD (100%) abiraterone in a fasted state for two weeks followed by two weeks of
500 mg QD (50%) abiraterone together with a standardized continental breakfast.
PK assessment will be performed after 2 (1000mg QD without food) and 4 weeks
(500mg QD with food) of abiraterone therapy. The results of these three
patients will be analysed and discussed to determine a safe and feasible dose
for the next patients in the study. The next 21-24 patienten will be randomized
into to groups. One group will start with 1000mg abirateron taken in a fasted
state, after two weeks of therapy they will switch to a reduced dose ingested
with a continental breakfast. the second group starts with the reduced dose
ingested with food and switches to 1000mg abirateron ingested fasted. The
reduced dose for the next 21-24 patients will either be 750mg QD (75%), 500mg
QD (50%) or 250mg QD (25%) based on the PK assessment and the safety profile
observed in the initial three patients.

Participating patients will be asked for a hospital admission for two days to
collect the blood samples. All blood samples will be drawn from a once placed
intravenous cannula. A total of 11 blood samples will be taken per admission
day. The burden for the participants of this part of the study is considered to
be mild.
In general the risk for participation in this study is regarded moderate.
The risk of suboptimal dosing is minimized by the run in of three patients at
500 mg QD with food and the very limited period in which the dose is reduced (2
weeks in total). Furthermore previous studies showed a food effect of at least
200% when ingested with a meal. The risk of abiraterone related toxicity is
very limited because previous studies showed no adverse events of >= grade 3
where seen when 1000mg abiraterone acetate was ingested with a high fat meal of
a period of one week. Benefits associated with participating in this study are
that patients and their treating physician get insight into their individual
abiraterone exposure and the abiraterone exposure when taken with a continental
breakfast.