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

Abstract

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.

Evaluation of the absolute oral bioavailability of the anaplastic lymphoma kinase/c-ROS oncogene 1 kinase inhibitor lorlatinib in healthy participants

“…h hour(s), IV intravenous, LLOQ lower limit of quantification by inducers or inhibitors of CYP3A. For example, plasma exposure was significantly reduced when co-administered with the strong CYP3A inducer rifampicin (AUC inf reduction of 85%) and the moderate CYP3A inducer modafinil (AUC inf reduction of 23%) [9,10]. Similarly in a study with the strong CYP3A inhibitor, itraconazole, plasma exposure of lorlatinib was increased (AUC inf increase of 42%) [8].…”

“…The recommended phase 2 dose of lorlatinib was determined to be 100 mg administered orally once daily based on the totality of safety, efficacy, and clinical pharmacology data [12]. Lorlatinib has been well-tolerated in clinical studies following multiple dosing in patients with NSCLC (single doses up to 200 mg) and in healthy volunteers (up to 100 mg) [2,3,[8][9][10][11][12]. Hence, for the oral treatment, a 100 mg single oral dose in healthy participants was utilised in this study.…”

“…The plasma PK of lorlatinib is not affected in a clinically meaningful manner by food or the co-administration of the proton pump inhibitor, rabeprazole [6]. However, lorlatinib plasma exposure can be affected by inducers or inhibitors of CYP3A [8][9][10].…”

Evaluation of the Effect of Lorlatinib on CYP2B6, CYP2C9, UGT, and P-Glycoprotein Substrates in Patients with Advanced Non-Small Cell Lung Cancer

“…Rifampin, a strong CYP3A4/5 inducer, reduced lorlatinib mean AUC ∞ and C max by 85% and 76%, respectively, and also caused elevated liver enzyme levels in the blood [ 10 ]. Modafinil, a moderate CYP3A4/5 inducer, also decreased the plasma exposure of lorlatinib, but to a lesser extent (23% and 22% reduction in lorlatinib AUC ∞ and C max , respectively) [ 26 ]. The use of lorlatinib with strong CYP3A4/5 inhibitors is contraindicated due to the aforementioned liver enzyme elevations with concomitant use.…”

Hallmarks of Anaplastic Lymphoma Kinase Inhibitors with Its Quick Emergence of Drug Resistance

“…5 Inspired, lorlatinib, approved by the Food and Drug Administration (FDA) in 2018, is a third-generation macrocyclic ALK inhibitor for ALK/ROS1 cancer therapy. It is a second-line treatment for patients with advanced ALK-positive NSCLC, 6 and becomes a first-line treatment for the disease in March 2021. 7 Originally, ALK was discovered in 1994 in anaplastic largecell lymphomas (ALCLs) as a part of nucleophosmin (NPM)-ALK fusion protein.…”