Summary
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.
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References
Lorbrena® (lorlatinib) tablets. [Prescribing Information]. Pfizer Labs
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):1590–1599
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):1654–1667
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)
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)
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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.
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Maulik Patel and Sunil Nepal were employees of Pfizer at the time the work was conducted.
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Patel, M., Chen, J., McGrory, S. et al. The effect of itraconazole on the pharmacokinetics of lorlatinib: results of a phase I, open-label, crossover study in healthy participants. Invest New Drugs 38, 131–139 (2020). https://doi.org/10.1007/s10637-019-00872-7
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DOI: https://doi.org/10.1007/s10637-019-00872-7