abstract
BACKGROUND:
The
oral, potent poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, is
well tolerated at doses of ≤400 mg twice daily (BID) (administered as
capsules), and has shown efficacy in patients with advanced BRCA-mutated
ovarian and breast cancer.
METHODS:
This
Phase I, open-label, randomized trial investigates the effect of food
on the pharmacokinetics of olaparib in patients with
refractory/resistant advanced solid tumors. In Part A, a three-period
crossover study, patients received a single oral dose of olaparib 400 mg
(8 × 50 mg capsules) in three prandial states: fasted, a high-fat meal
or a standard meal (with a 5-14 day washout). Blood samples for
pharmacokinetic (PK) assessments were taken pre-dose and up to 72 h
post-dose. After completing Part A, patients could enter Part B, where
they would receive olaparib 400 mg BID.
RESULTS:
32
patients were randomized; 31 contributed to the PK statistical analysis
and entered Part B. The presence of food slowed the rate of absorption
(time to maximal plasma concentration [t max] was delayed by ~2 h). Maximum plasma concentration (C max)
was increased by 10% following a standard meal and was unchanged with a
high-fat meal (ratio of geometric means [90% confidence interval (CI)]:
1.10 [1.02-1.20] for standard and 1.00 [0.92-1.09] for high-fat meal).
The extent of olaparib absorption (AUC) was increased by ~20% in the fed
state (ratio of geometric means: 1.21 [1.10-1.33] for standard and 1.19
[1.08-1.31] for high-fat meal).
CONCLUSIONS:
The
presence of food decreased the rate and increased the extent of
absorption of olaparib following oral dosing of the capsule formulation.
However, the effects of food on olaparib PK were not deemed clinically
important, according to predefined criteria. Safety data were consistent
with the known safety profile of olaparib.
FUNDING:
AstraZeneca.
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