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

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 (C_trough,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 AUC_0–24h 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 AUC_0–∞ 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 AUC_0–24h 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.

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