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

Abstract

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.

A Proposal of Conducting Bioequivalence Trials with Gastric pH Modulators for Two Oral Formulations Demonstrating Different Dissolution Profiles at Elevated pH

“…The trial showed an average of 80% reduction in palbociclib C max in subjects stabilized with rabeprazole. The observed palbociclib C max for all subjects stabilized with rabeprazole were similar to that from the subgroup of subjects showing low exposure in other phase I trials . Furthermore, four subjects who showed low exposure receiving the palbociclib free base formulation alone demonstrated no further exposure change when receiving palbociclib in combination with rabeprazole…”

“…When the pH is <4.3, the solubility of palbociclib is >0.5 mg/mL, which means that 125 mg of palbociclib free base can be completely dissolved in 250 mL of buffer. However, the solubility drastically decreases when the pH increases, approaching zero near pH 7 . Along with the solubility changes, the dissolution rate and extent, as illustrated in Figure a , are significantly decreased when pH increases.…”

“…Palbociclib, as a weak organic base, is indicated for the treatment of breast cancer . Two formulations using different active pharmaceutical ingredients (APIs) were developed at different stages during clinical development . The early clinical trials used an isethionate salt formulation.…”

“…The early clinical trials used an isethionate salt formulation. A free base formulation was developed for subsequent clinical trials and commercialization . A crossover bioequivalence trial was conducted to bridge the free‐base and the isethionate salt formulations.…”

“…In addition, it was found that the subjects with low exposure did not represent the majority of the subjects, because the median exposures in the free‐base formulation group were similar to those from other formulation groups. The subjects showing low exposure accounted for 13% of the total subjects receiving the free base formulation …”