The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, Open-Label, Crossover S
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ORIGINAL RESEARCH
The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, OpenLabel, Crossover Study in Healthy Participants Joseph Chen
. Huiping Xu . Sylvester Pawlak . Leonard P. James .
Gerson Peltz . Kimberly Lee . Katherine Ginman . Michelle Bergeron . Yazdi K. Pithavala
Received: October 31, 2019 Ó Springer Healthcare Ltd., part of Springer Nature 2019
ABSTRACT Introduction: Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung Enhanced Digital Features To view enhanced digital features for this article go to https://doi.org/10.6084/ m9.figshare.11342396. Electronic Supplementary Material The online version of this article (https://doi.org/10.1007/s12325019-01198-9) contains supplementary material, which is available to authorized users. J. Chen (&) L. P. James Global Product Development, Pfizer Oncology, New York, NY, USA e-mail: [email protected] H. Xu Y. K. Pithavala Global Product Development, Clinical Pharmacology, Pfizer Oncology, La Jolla, CA, USA S. Pawlak Global Product Development, Pfizer Inc., New Haven, CT, USA G. Peltz Safety Surveillance and Risk Management, Pfizer Oncology, Groton, CT, USA K. Lee M. Bergeron Global Product Development, Pfizer Inc., Groton, CT, USA K. Ginman Global Product Development, Pfizer Inc., South Lyon, MI, USA
cancer; cytochrome P450 (CYP) 3A plays an important role in the metabolism of lorlatinib. Methods: 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. Results: 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. Conclusions: The addition of a single dose of lorlatinib to daily dosing with rifampin
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significantly reduced lorlatinib plasma exposure relative to a single dose of lorlatinib administered alone and was associated with severe but self-limiting transaminase eleva
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