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

Adv Ther. 2020 Feb;37(2):745-758. doi: 10.1007/s12325-019-01198-9. Epub 2019 Dec 20.

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 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 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.

Keywords: Drug–drug interaction; Healthy participants; Lorlatinib; Pharmacokinetics; Rifampin; Safety.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aminopyridines
  • Antineoplastic Agents / therapeutic use*
  • Area Under Curve
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Cross-Over Studies
  • Drug Interactions
  • Female
  • Healthy Volunteers
  • Humans
  • Lactams
  • Lactams, Macrocyclic / pharmacokinetics*
  • Lactams, Macrocyclic / therapeutic use*
  • Lung Neoplasms / drug therapy*
  • Male
  • Middle Aged
  • Pyrazoles
  • Rifampin / pharmacokinetics*
  • Rifampin / therapeutic use*
  • Young Adult

Substances

  • Aminopyridines
  • Antineoplastic Agents
  • Lactams
  • Lactams, Macrocyclic
  • Pyrazoles
  • lorlatinib
  • Rifampin

Associated data

  • figshare/10.6084/m9.figshare.11342396
  • ClinicalTrials.gov/NCT02804399