Phase 1 Study Evaluating the Effects of the Proton Pump Inhibitor Rabeprazole and Food on the Pharmacokinetics of Lorlatinib in Healthy Participants

Abstract

Lorlatinib is approved worldwide as treatment for anaplastic lymphoma kinase-positive and c-ros oncogene 1-positive non-small cell lung cancer. The objectives of this phase 1, open-label crossover study (NCT02569554) in healthy adult participants were to determine (1) the effects of the proton pump inhibitor (PPI) rabeprazole on lorlatinib pharmacokinetics (PK), (2) the effects of a high-fat meal on lorlatinib PK, and (3) the relative bioavailability of an oral solution to tablet formulation of lorlatinib under fasted conditions. Participants were followed on-study for ≥50 days after the first dose of lorlatinib. Participants received treatments over 4 periods, with a washout of ≥10 days between consecutive lorlatinib doses. Twenty-seven participants were enrolled and received lorlatinib, and all were assessed for PK and safety. Results showed no effect of multiple doses of rabeprazole on the total plasma exposure of a single oral dose of lorlatinib 100-mg tablets. The results also indicated that a high-fat meal had no effect on lorlatinib PK after a single 100-mg oral dose. In addition, the relative bioavailability of lorlatinib oral solution compared with lorlatinib tablets was complete (approximately 108%). The safety profile of lorlatinib was consistent with that reported in previous studies, and most treatment-related adverse events were mild to moderate. These data indicate that lorlatinib can be administered with drugs that modify gastric acid, including PPIs, without restriction. These results also confirm that lorlatinib can be administered regardless of food intake.

Trial registration: ClinicalTrials.gov NCT02630706.

Keywords: drug-drug interactions; drug-food interactions; food effect; lorlatinib; pharmacokinetics and drug metabolism; proton pump inhibitor; rabeprazole.

Conflict of interest statement

H.X. is a full‐time employee and current stockholder at Pfizer Inc. M.T.O. is a full‐time employee and may hold stock or stock options in Pfizer Inc. S.N. was an employee of Pfizer Inc. at the time this research was conducted and may hold stock or stock options in Pfizer Inc. L.P.J. was an employee of Pfizer Inc. at the time this research was conducted, and is a current stockholder at Pfizer Inc. He holds current employment with Bristol‐Myers Squibb. K.G. is a full‐time employee and current stockholder at Pfizer Inc. Y.K.P. is a full‐time employee and current stockholder at Pfizer Inc.

© 2021 Pfizer Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Mean plasma lorlatinib concentration‐versus‐time profiles following single oral doses. (A) Linear plot. (B) Semilogarithmic plot.

Figure 2

Individual and mean plasma lorlatinib AUCinf (A) and Cmax (B). Stars represent the arithmetic means, the open circles represent individual values, and the bars are the standard deviations. AUCinf, area under the plasma concentration‐versus‐time curve from time 0 to infinity; Cmax, maximum observed plasma concentration.

Figure 3

Individual plasma lorlatinib plots of AUCinf and Cmax for lorlatinib 100‐mg tablets versus lorlatinib 100‐mg tablets + a high‐fat meal (A and B) and lorlatinib 100‐mg tablets versus lorlatinib + rabeprazole 20 mg (C and D). Diamonds represent the geometric mean, and stars represent the arithmetic mean. AUCinf, area under the plasma concentration‐versus‐time curve from time 0 to infinity; Cmax, maximum observed plasma concentration.