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

• Published in: Advances in therapy Vol. 37; no. 2; pp. 745 - 758
• Main Authors: Chen, Joseph, Xu, Huiping, Pawlak, Sylvester, James, Leonard P., Peltz, Gerson, Lee, Kimberly, Ginman, Katherine, Bergeron, Michelle, Pithavala, Yazdi K.
• Format: Journal Article
• Language: English
• Published: Cheshire Springer Healthcare 01-02-2020
• Subjects: Cardiology; Endocrinology; Internal Medicine; Medicine; Medicine & Public Health; Oncology; Original Research; Pharmacology/Toxicology; Rheumatology; Safety; Lorlatinib; Pharmacokinetics; Rifampin; Drug–drug interaction; Healthy participants
• ISSN: 0741-238X; 1865-8652
• DOI: 10.1007/s12325-019-01198-9

Introduction
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.
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 (AUC
inf
) and maximum plasma concentration (
C
max
) 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 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
ClinicalTrials.gov identifier, NCT02804399.