Assessment of drug-drug interaction potential between ceritinib and proton pump inhibitors in healthy subjects and in patients with ALK-positive non-small cell lung cancer

Cancer Chemother Pharmacol. 2017 Jun;79(6):1119-1128. doi: 10.1007/s00280-017-3308-7. Epub 2017 Apr 19.

Abstract

Purpose: The impact of proton pump inhibitors (PPIs) on the pharmacokinetics (PK) and efficacy of ceritinib was evaluated.

Methods: A healthy subject drug-drug interaction (DDI) study was conducted to assess the effect of esomeprazole on the PK of a single 750 mg dose of ceritinib. To further investigate the impact of PPIs on the PK and efficacy of ceritinib in ALK-positive cancer patients, two subgroup analyses were performed. Analysis 1 evaluated ceritinib steady-state trough concentration (Ctrough,ss) and overall response rate (ORR) by concomitant use of PPIs in patients from the ASCEND-1, -2, and -3 studies; analysis 2 evaluated ceritinib single-dose and steady-state AUC0-24h and C max by concomitant PPI use in patients from ASCEND-1 using a definition of PPI usage similar to that used in the healthy subject study.

Results: In the healthy subject study, co-administration of a single 750 mg dose of ceritinib with esomeprazole 40 mg for 6 days decreased ceritinib AUC0-∞ by 76% and C max by 79%. However, based on subgroup analysis 1, patients had similar C trough,ss and ORR regardless of concomitant PPI usage. Based on analysis 2, co-administration of a single 750 mg ceritinib dose with PPIs for 6 days in patients suggested less effect on ceritinib exposure than that observed in healthy subjects as AUC0-24h decreased by 30% and C max decreased by 25%. No clinically meaningful effect on steady-state exposure was observed after daily dosing.

Conclusions: Long-term administration of ceritinib with PPIs does not adversely affect the PK and efficacy of ceritinib in ALK-positive cancer patients.

Keywords: Anaplastic lymphoma kinase; Ceritinib; Drug–drug interactions; Esomeprazole; Proton pump inhibitors.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adolescent
  • Adult
  • Anaplastic Lymphoma Kinase
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / therapeutic use
  • Area Under Curve
  • Carcinoma, Non-Small-Cell Lung / complications*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Drug Interactions
  • Esomeprazole / pharmacokinetics*
  • Esomeprazole / therapeutic use
  • Female
  • Healthy Volunteers
  • Humans
  • Lung Neoplasms / complications*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Male
  • Middle Aged
  • Protein Kinase Inhibitors / pharmacokinetics*
  • Protein Kinase Inhibitors / therapeutic use
  • Proton Pump Inhibitors / pharmacokinetics*
  • Proton Pump Inhibitors / therapeutic use
  • Pyrimidines / pharmacokinetics*
  • Pyrimidines / therapeutic use
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Sulfones / pharmacokinetics*
  • Sulfones / therapeutic use
  • Treatment Outcome
  • Young Adult

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Proton Pump Inhibitors
  • Pyrimidines
  • Sulfones
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases
  • ceritinib
  • Esomeprazole