The effect of itraconazole on the pharmacokinetics of lorlatinib: results of a phase I, open-label, crossover study in healthy participants
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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.
KeywordsDrug-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.
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 was obtained from all individual participants included in the study.
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Upon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results 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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