Effect of the moderate CYP3A4-inhibitor erythromycin on the pharmacokinetics of palbociclib

Palbociclib is an inhibitor of cyclin-dependent kinase 4 (CDK4) and CDK6,
indicated for the treatment of hormone receptor positive, Her2 negative,
locally advanced or metastatic breast cancer. Palbociclib exposure has been
linked to toxicity, with a higher area under the concentration-time curve (AUC)
being associated with a greater reduction in absolute neutrophil count. Common
adverse reactions reported in patients receiving palbociclib are also fatigue,
nausea, stomatitis and diarrhoea (>=20%), which can seriously hamper quality of
life.

Palbociclib is metabolized by CYP3A4 and its exposure was significantly
increased when co-administered with itraconazole (a strong CYP3A4 inhibitor),
resulting in an increase in AUC0-inf and Cmax of 87% and 34%, respectively.
Therefore, it is advised to avoid concomitant use of strong CYP3A4 inhibitors.
If co-administration with a strong CYP3A4 inhibitor cannot be avoided, the
daily palbociclib dose should be reduced to 75 mg (60% of standard dose).
Although it is recommended by the FDA to evaluate the impact of moderate
inhibitors in the case of clinically significant interactions with strong
inhibitors, no management guidelines for concomitant use of palbociclib with
moderate CYP3A4 inhibitors have been reported.[2]

Yu et al published an physiologically based pharmacokinetic (PBPK) model, in
which they simulated the effect of the moderate CYP3A4 inhibitors verapamil and
diltiazem. They reported an increase in AUC and Cmax of 38% and 22% for
verapamil; and 42% and 23% for diltiazem, respectively. The authors conclude
that the risk of drug-drug interactions for palbociclib co-administered with
moderate CYP3A4 inhibitors is relatively modest and that no dose adjustment is
needed. However, a 40% increase in exposure could be clinically relevant, since
higher palbociclib exposure is associated with increased toxicity like fatigue,
nausea, stomatitis and diarrhoea which can seriously hamper quality of life
(not only lab abnormalities).

Based on the above, we propose to conduct a randomized pharmacokinetic
cross-over trial to study the effect of the moderate CYP3A4 inhibitor
erythromycin on the pharmacokinetics of palbociclib. This study will provide
enough data to guide future physicians and patients on dosing instructions and
adverse events expectations when in daily care palbociclib is given to patients
using a moderate CYP3A4 inhibitor.

The primary objective of this trial is to study the effect of the moderate
CYP3A4 inhibitor erythromycin on the pharmacokinetics of palbociclib, measured
as AUC0-24h, Cmax and Cmin.
The secondary objective of this trial is to compare the incidence and severity
of adverse events with (a week) and without co-administration of the moderate
CYP3A4 inhibitor erythromycin, according to CTC-AE v5.0.

Randomized pharmacokinetic cross-over trial of palbociclib with and without
erythromycin

Palbociclib will be administered concomitant with erythromycin during 7 days of
the study.

Patients will receive the standard dose of palbociclib (125 mg QD, 3-weeks on
1-week off) at all times during the study. Theoretically, the concomitant
administration of palbociclib with erythromycin could lead to higher
palbociclib exposure and thus give an increased risk of toxicities. However,
the duration of this intervention is short (7 days).

Although erythromycin rarely gives toxicities, this is a minor risk for
patients.

Since erythromycin could prolong the QTc interval, an ECG will be performed at
screening. Patients with a prolonged QTc interval will be excluded.

In total, 28 PK samples of 3 mL will be drawn (14 samples at both Day 7 and Day
21).