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The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, Open-Label, Crossover Study in Healthy Participants

A Correction to this article was published on 10 September 2020

This article has been updated



Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer; cytochrome P450 (CYP) 3A plays an important role in the metabolism of lorlatinib.


This phase 1, open-label, two-period, crossover study estimated the effect of oral rifampin (a strong CYP3A inducer) on the pharmacokinetics and safety of oral lorlatinib (NCT02804399). Healthy participants received single-dose lorlatinib 100 mg in period 1 followed by rifampin 600 mg/day (days 1–12) and single-dose lorlatinib 100 mg (day 8) in period 2. Blood samples were collected for 120 h after each dose of lorlatinib.


When a single dose of lorlatinib was administered during daily dosing with rifampin (period 2), the area under the plasma concentration-time profile extrapolated to infinity (AUCinf) and maximum plasma concentration (Cmax) of lorlatinib were 14.74% [90% confidence interval (CI) 12.78%, 17.01%] and 23.88% (90% CI 21.58%, 26.43%), respectively, of those in period 1 (lorlatinib alone). A single dose of lorlatinib was well tolerated in period 1, but elevations in transaminase values were observed in all participants (grade 2–4 in 11 participants) within 1–3 days after a single dose of lorlatinib was administered with ongoing rifampin in period 2. Rifampin dosing was therefore halted. Transaminase levels subsequently returned to normal (median time to recovery: 15 days). No elevations in bilirubin were observed.


The addition of a single dose of lorlatinib to daily dosing with rifampin significantly reduced lorlatinib plasma exposure relative to a single dose of lorlatinib administered alone and was associated with severe but self-limiting transaminase elevations in all healthy participants. These observations support the contraindication in the product label against concomitant use of lorlatinib with all strong CYP3A inducers.

Trial registration identifier, NCT02804399.

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Pfizer Inc. and the authors thank the volunteers who participated in this study and the investigators for their contributions.


Pfizer Inc. sponsored the study, contributed to the design, and participated in the collection, analysis, and interpretation of the data and in the writing, reviewing, and final approval of the publication. The Rapid Service Fee was funded by Pfizer Inc.

Medical Writing and/or Editorial Assistance

Statistical support was provided by Sunil Nepal and Melissa O’Gorman of Pfizer Inc. Editorial support was provided by Blair Jarvis and Kate Williams and Gayle Scott of inScience Communications, Springer Healthcare (Chester, UK), and was funded by Pfizer Inc.


All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.


Katherine Ginman is an employee of Pfizer. Joseph Chen, Huiping Xu, Sylvester Pawlak, Gerson Peltz, Kimberly Lee, and Michelle Bergeron are emoloyees of Pfizer and own stocks in Pfizer. Yazdi K Pithavala is an employee of Pfizer, owns stock in Pfizer and has patents with Pfizer. Leonard P James owns stocks in Pfizer. At the time of the study Leonard P James was an employee of Pfizer and is currently an employee of Bristol-Myers Squibb.

Compliance with Ethics Guidelines

The study was conducted in compliance with the principles in the Declaration of Helsinki and in compliance with International Conference on Harmonization Good Clinical Practice Guidelines. The protocol was approved by the Institutional Review Board at the study center (IntegReview IORG0000689). All participants provided written informed consent before undergoing any study procedures. In addition, after the trial was under way, all participants re-consented to allow for additional analyses of blood samples.

Data Availability

Upon request, and subject to certain criteria, conditions, and exceptions (see for more information), Pfizer will provide access to individual deidentified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The deidentified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.

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Chen, J., Xu, H., Pawlak, S. et al. The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, Open-Label, Crossover Study in Healthy Participants. Adv Ther 37, 745–758 (2020).

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  • Drug–drug interaction
  • Healthy participants
  • Lorlatinib
  • Pharmacokinetics
  • Rifampin
  • Safety