The effect of itraconazole on the pharmacokinetics of lorlatinib: results of a phase I, open-label, crossover study in healthy participants

  • Maulik PatelEmail author
  • Joseph Chen
  • Stephanie McGrory
  • Melissa O’Gorman
  • Sunil Nepal
  • Katherine Ginman
  • Yazdi K. Pithavala


Background The third-generation tyrosine kinase inhibitor lorlatinib is approved for the treatment of ALK-positive metastatic NSCLC. CYP3A plays a major role in lorlatinib metabolism; therefore, a drug-drug interaction study was warranted to evaluate the impact of the strong CYP3A inhibitor, itraconazole, on lorlatinib plasma exposure. Methods This phase 1, open-label, 2-period, crossover study estimated the effects of itraconazole on the plasma pharmacokinetics and safety of lorlatinib in healthy participants (NCT02838264). Single-dose lorlatinib 50 mg (n = 2), 75 mg (n = 2) and 100 mg (n = 12) was administered in Period 1. In Period 2, itraconazole oral solution 200 mg/day was administered on Days 1−11, and single-dose lorlatinib on Day 5. Blood samples were collected up to 168 h after lorlatinib dosing. Results During daily dosing with itraconazole (Period 2), the ratios of the adjusted geometric means for area under the plasma concentration-time profile extrapolated to infinity (AUCinf) and maximum plasma concentration (Cmax) of single-dose lorlatinib 100 mg were 141.79% (90% confidence interval, 128.71%, 156.21%) and 124.39% (110.20%, 140.41%), respectively, compared with Period 1 (lorlatinib alone). Lorlatinib was well tolerated alone and with itraconazole. No serious adverse events or withdrawals were reported. Conclusions Co-administration of itraconazole and lorlatinib increased the plasma exposure of lorlatinib relative to lorlatinib alone in healthy participants. Therefore, concomitant use of lorlatinib with strong CYP3A inhibitors should be avoided. If this combination is unavoidable, the starting dose of lorlatinib should be reduced from 100 mg to 75 mg.


Drug-drug interaction Healthy participants Itraconazole Lorlatinib Pharmacokinetics Phase 1 trial 



Editorial support was provided by Blair Jarvis and Kate Williams of inScience Communications, Springer Healthcare (Chester, UK) and was funded by Pfizer Inc.


This study was sponsored by Pfizer Inc.

Compliance with ethical standards

Conflict of interest

MP is an employee of AbbVie Inc. and owns stock in AbbVie Inc.

JC is an employee of Pfizer Inc. and owns stock in Pfizer Inc.

SM is an employee of Pfizer Inc. and owns stock in Pfizer Inc.

MO is an employee of Pfizer Inc.

SN is an employee of Pfizer Inc.

KG is an employee of Pfizer Inc.

YKP is an employee of Pfizer Inc. and owns stock in Pfizer Inc.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Ethics Committee of Erasme Hospital, Anderlecht, Belgium) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Data sharing statement

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.

Supplementary material

10637_2019_872_MOESM1_ESM.pdf (159 kb)
ESM 1 (PDF 159 kb)


  1. 1.
    Lorbrena® (lorlatinib) tablets. [Prescribing Information]. Pfizer LabsGoogle Scholar
  2. 2.
    Shaw AT, Felip E, Bauer TM et al (2017) Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol 18(12):1590–1599CrossRefGoogle Scholar
  3. 3.
    Solomon BJ, Besse B, Bauer TM et al (2018) Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol 19(12):1654–1667CrossRefGoogle Scholar
  4. 4.
    Stypinski D, Fostvedt L, Lam J, et al. Metabolism, excretion and pharmacokinetics of lorlatinib (PF-06463922; Lorbrena®) and evaluation of the impact of radiolabel location and other factors on comparability of data across two ADME studies (manuscript in development)Google Scholar
  5. 5.
    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 subjects (manuscript in development)Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Maulik Patel
    • 1
    • 2
    Email author
  • Joseph Chen
    • 3
  • Stephanie McGrory
    • 4
  • Melissa O’Gorman
    • 5
  • Sunil Nepal
    • 4
  • Katherine Ginman
    • 6
  • Yazdi K. Pithavala
    • 7
  1. 1.Pfizer Inc.La JollaUSA
  2. 2.AbbVieRedwood CityUSA
  3. 3.Pfizer OncologyNew YorkUSA
  4. 4.Pfizer Inc.CollegevilleUSA
  5. 5.Pfizer OncologyGrotonUSA
  6. 6.Pfizer Inc.South LyonUSA
  7. 7.Pfizer OncologyLa JollaUSA

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