Effect of 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.

Erythromycin significantly increase the pharmacokinetic exposure of palbociclib

Pharmacokinetic sampling will be performed at Day 7 and Day 21 of the study (palbociclib alone vs. palbociclib + erythromycin, sequence depending on randomization) at the following timepoints: predose, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 24 hours postdose.

Patients will use erythromycin 500 mg TID during one week concomitant with palbociclib.