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.

Conflict of interest statement

Jerry Li, Yazdi K. Pithavala, Jason Gong, Robert R. LaBadie, Josué Kunjom Mfopou, and Joseph Chen are employees of Pfizer Inc. and may own stock and/or stock options in Pfizer.

© 2021. The Author(s).

Figures

Fig. 1

Line plots of individual participant and median liver function tests: a aspartate aminotransferase (AST), b alanine aminotransferase (ALT), c alkaline phosphatase (ALP), and d total bilirubin, for the 100-mg cohort (Cohorts 3 and 4 combined). The red dashed lines on the figures represent the upper limit of normal (ULN) for AST (40 U/L), ALT (49 U/L), ALP (111 U/L), and total bilirubin (1.2 mg/dL), respectively. Study day 1 = Period 1 day 1; day 6 = Period 1 day 6/Period 2 day 1; day 20 = Period 2 day 15. Age-adjusted ULN of 127 U/L for ALP was applicable to a 55-year-old participant who completed the study in Cohort 4. QD once daily

Fig. 2

a Plasma lorlatinib and b metabolite (M8) concentration–time profiles for the 100-mg cohort (Cohorts 3 and 4 combined) following administration of a single oral dose of lorlatinib alone and in the presence of steady-state modafinil. QD once daily

Fig. 3

Matchstick plots for plasma 4β-hydroxycholesterol/cholesterol ratios (molar ratios × 10− 5) pre-modafinil and post-modafinil once-daily treatments. Only participants who had at least one plasma 4β-hydroxycholesterol/cholesterol ratio are represented. Data represent individual participant values (participants 1 and 2 were in Cohort 1 [lorlatinib 50 mg], participants 3 and 4 were in Cohort 2 [lorlatinib 75 mg], and participants 5–16 were in Cohorts 3 and 4 combined (lorlatinib 100 mg])