The Effect of Modafinil on the Safety and Pharmacokinetics of Lorlatinib: A Phase I Study in Healthy Participants

Background and Objective Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the second-line treatment of patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer. Lorlatinib is metabolized by cytochrome P450 (CYP) 3A and contraindicated with strong CYP3A inducers because of significant transaminase elevation. This phase I, open-label, two-period study evaluated the impact of a moderate CYP3A inducer, modafinil, on the safety and pharmacokinetics of lorlatinib. Methods Healthy participants received single-dose oral lorlatinib (50 mg [ n = 2], 75 mg [ n = 2], or 100 mg [ n = 2 + 10 in an expanded cohort]) in Period 1 followed by modafinil 400 mg/day (days 1–19) and single-dose lorlatinib (day 15, same dose as previous) both orally in Period 2. Blood samples were collected for 120 h after each dose of lorlatinib. Results Of 16 participants, ten completed the study; six participants, all in the expanded 100-mg cohort, discontinued because of adverse events during the modafinil lead-in dosing period. Single doses of lorlatinib 50–100 mg were well tolerated when administered alone and in the presence of steady-state modafinil. Of the ten participants who completed the study, all had transaminase values within normal limits during the combination of lorlatinib with modafinil. The ratios of the adjusted geometric means (90% confidence interval) for lorlatinib area under the plasma concentration–time profile extrapolated to infinity and maximum plasma concentration were 76.69% (70.15–83.83%) and 77.78% (65.92–91.77), respectively, when lorlatinib 100 mg was co-administered with steady-state modafinil compared with lorlatinib administration alone. Conclusion Lorlatinib 100 mg may be safely co-administered with moderate CYP3A inducers. Clinical Trial Registration ClinicalTrials.gov NCT03961997; registered 23 May, 2019.