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. Keywordsdrug-drug interactions, drug-food interactions, food effect, lorlatinib, pharmacokinetics and drug metabolism, proton pump inhibitor, rabeprazole Small-molecule tyrosine kinase inhibitors (TKIs) of anaplastic lymphoma kinase (ALK) are used to treat patients with advanced or metastatic non-small cell

Dynamic Changes in Gastrointestinal Fluid Characteristics after Food Ingestion Are Important for Quantitatively Predicting the In Vivo Performance of Oral Solid Dosage Forms in Humans in the Fed State

“…Figure c and Table show the predicted PK profiles and PK parameters, respectively, of lorlatinib in the fasted and fed state in humans. C max and AUC values in the fasted and fed (Models 1–4) states in our simulations were similar to the respective observed values in humans . Food ingestion did not significantly affect the in vivo performance of the drug formulation in humans, and our simulation approaches successfully predicted these no food effects, regardless of the model assumption in the fed state.…”

“…All drugs were purchased on the Japanese market. According to previous reports, food ingestion has no effect on Glivec and Lobrena , but decreases the oral absorption of Tafinlar and Jakavi , and increases that of Tasigna and Tykerb. , Based on the BCS, imatinib is a class 1 drug, lorlatinib is a class 4 drug, dabrafenib is a class 2 drug, ruxolitinib is a class 1 drug, and nilotinib and lapatinib are class 4.…”

“…Figure 3. Dissolution profiles of lorlatinib in (a) simulated gastric fluids and (b) simulated intestinal fluids, and (c) the predicted PK profiles of lorlatinib in humans compared with observed data 16. …”