Impact of Acid‐Reducing Agents on the Pharmacokinetics of Palbociclib, a Weak Base With pH‐Dependent Solubility, With Different Food Intake Conditions

Palbociclib free base capsule is a weak base drug with highly pH-dependent solubility. In vitro and in vivo studies evaluated the impact of acid-reducing agents on exposure of palbociclib and determined whether the impact, if any, can be mitigated by food. A drug-drug interaction study (study 1) was conducted first under fasted conditions and showed that coadministration of multiple doses of the proton-pump inhibitor rabeprazole substantially reduced palbociclib mean area under the concentration-time curve from time 0 to infinity and maximum observed plasma concentration by 62% and 80%, respectively. In vitro assessment suggested that the presence of bile salt mixed micelles to mimic the fed state can significantly enhance the solubility of palbociclib. Subsequently, study 2 was conducted under fed conditions and demonstrated that coadministration of rabeprazole decreased palbociclib maximum observed plasma concentration by 41% but had limited impact on area under the concentration-time curve from 0 to infinity (13% decrease). This study also showed that the histamine-2 receptor antagonist famotidine and local antacid with staggered dosing had no impact on palbociclib exposure under fed conditions. Food intake effectively mitigated the impact of acid-reducing agents on palbociclib exposure. Palbociclib free base capsule should be taken with food, and acid-reducing agent use does not need to be avoided.