The food-effect of a standardized Dutch breakfast on the pharmacokinetics of oral alectinib (Alecensa®) using a stable isotopically labelled microtracer approach

Alectinib (Alecensa®) is a highly selective inhibitor of anaplastic lymphoma
kinase (ALK) [1]. Its efficacy against oncogenic ALK fusion gene-rearrangements
(ALK-positive) and good penetration through the blood-brain-barrier makes
alectinib an effective agent against ALK-positive non-small cell lung cancer
(NSCLC) [1]. Alectinib is recommended as first-line treatment of ALK-positive
NSCLC [2]. The registered dose is 600 mg bidaily (BID) in Western countries [1]
and patients are recommended to administer their daily alectinib doses with
food [3].

The advice to administer alectinib with food is based on the results from a
cross-over, food-effect study in 18 healthy volunteers [4]. Subjects received a
single oral dose of 600 mg alectinib in a fasted state and a fed state [4]. In
the fed state, patients received a standardized high-calorie, high-fat meal
containing 900 calories (56% of fat) [4]. The maximum concentration (Cmax) and
Area-under-the-concentration-time-Curve (AUC) increased with 2.7- and 2.92-fold
in the fed state compared to the fasted state [4].

The standardized breakfast used in the above described study is conform
guidelines for food-effect studies by the European Medicines Agency (EMA) and
US Food and Drug administration (FDA) [5,6]. However, a high-calorie, high-fat
breakfast is not an accurate representation for the average Dutch breakfast
[7]. Furthermore, other studies have reported a moderate food-effect on
alectinib pharmacokinetics: reporting an elongated time to maximum
concentration (Tmax) [8] and an increase in Cmax and AUC0-t of approximately
20% [9]. Continuing, a recent retrospective study reported an inter-individual
variability of 57.2% and intra-individual variability of 27.0% in alectinib
pharmacokinetics [10]. Therefore, an increase in Cmax and AUC0-t of
approximately 20% is not clinically relevant.

Physiochemical properties of alectinib show low solubility and moderate
permeability, resulting in a moderate absolute bioavailability of 36.9% [11].
High fat constituents of food could increase alectinib solubility in the
intestines and thereby increase uptake. This could explain the difference in
food-effect seen after a high-calorie, high-fat meal in comparison to other
food-effect studies [8,9,4]. Furthermore, alectinib is majorly metabolized by
cytochrome P450 3A (CYP3A) to its major metabolite M4 [12]. M4 exhibits similar
active potency to alectinib and is therefore expected to contribute to the
efficacy of alectinib [1]. The previously described high-calorie, high-fat
breakfast increased the Cmax and AUCinf with 3.77 and 3.28 fold, respectively
[4]

The aim of this study is to determine the food-effect of a standardized Dutch
breakfast on the pharmacokinetics of alectinib. Despite the fact that three
studies have reported a food-effect on alectinib pharmacokinetics [4,8,9], it
is still unclear what the food-effect is on alectinib exposure in the daily
lives of patients. It is important to understand this effect due the high
inter- and intra-individual variability observed in alectinib exposure as well
as the observed exposure-response relationship [10]. Food might be a strategy
to increase exposure without dose increase or reduce intra-individual
variability.

A conventional, cross-over, food-effect study requires the participating
patients to administer the investigational drug with and without food over
several days until steady-state is reached (approximately 5 times the half-life
of the respective drug). When steady-state is reached, blood samples will be
collected for the determination of exposure of the investigational drug.
However, this study design is inappropriate for the determination of the
food-effect of alectinib due to possibly underexposure. A previously reported
exposure-response analysis reported significantly decreased survival for NSCLC
patients with an alectinib trough plasma concentrations (Ctrough) <435 ng/mL
[10]. Clinical trial simulations demonstrated that 55.5% of patients will have
Ctrough below the target when alectinib is administered under fasting
conditions assuming a food-effect of 40%.

A microtracer approach was chosen to determine the food-effect on alectinib
pharmacokinetics without influencing the therapeutic treatment. A microtracer
is a 100 µg dose of a stable isotopically labelled (SIL) drug [13]. These
microtracers have been used for the determination of absolute food-effect [13].
Due to the mass difference between the therapeutic administered drug and the
microtracer, the concentrations of both compounds can be simultaneously
quantified in the same sample.

To determine the food-effect of a standardised Dutch breakfast on the
pharmacokinetics of oral alectinib (Alecensa®), especially Cmax, AUC and
relative bioavailability, at steady state using a stable isotopically labelled
microtracer approach.

A prospective, single-center, open-label, food-effect stable isotopically
labelled microtracer study with oncology patients, who will receive an oral
dose of alectinib-d6. After obtaining informed consent, blood will be drawn for
pharmacokinetics after administration of alectinib-d6 in a fed state and a
fasted state (see Pharmacokinetics). The fed state consists of a standardised
Dutch breakfast (320-392 kCal, 7.5-7.8 gram fat). The fasted state consists of
an overnight fast of minimal 10 hours.

Patients will receive twice a 100 microgram dose of alectinib-d6 (microtracer).
The first dose will be administered with the standardized breakfast en de
second dose will be administered after a washout periode and an ovenright fast
of minimal 10 hours.

Patients participating will be hospitalized for 8 hours on two separate
occasions. Blood sampling for pharmacokinetic research will be done at 8 time
points. As alectinib-d6 is administered as a single low dose oral treatment, no
additional risk is expected to be associated with study participation.