Evaluation of the Effect of Lorlatinib on CYP2B6, CYP2C9, UGT, and P-Glycoprotein Substrates in Patients with Advanced Non-Small Cell Lung Cancer

Joseph Chen, Alessandra Bearz, Dong Wan Kim, Hirva Mamdani, Jessica Bauman, Rita Chiari, Sai Hong Ignatius Ou, Benjamin J. Solomon, Ross A. Soo, Enriqueta Felip, Alice T. Shaw, Holger Thurm, Jill S. Clancy, Kimberly Lee, Melissa O’Gorman, Cherie Tanski, Yazdi K. Pithavala

Research output: Contribution to journalArticlepeer-review

Abstract

Background and Objective: Lorlatinib is a tyrosine kinase inhibitor approved for the treatment of advanced anaplastic lymphoma kinase–positive non-small cell lung cancer. This study assessed the effect of steady-state lorlatinib on the metabolic enzymes cytochrome P450 (CYP) 2B6, CYP2C9, and uridine 5′-diphospho-glucuronosyltransferase (UGT) and the P-glycoprotein (P-gp) transporter. Methods: Thirty-two patients received a single oral dose of a probe drug on Day − 2 to determine the pharmacokinetics of the probe drug alone. Starting on Day 1, patients received 100 mg oral lorlatinib daily. On Day 15, a single oral dose of the probe drug was administered concurrently with lorlatinib. Pharmacokinetic parameters for these probe substrates were assessed. Results: Plasma exposures of all probe substrates were reduced by lorlatinib compared with the probe alone. The greatest reduction in area under the plasma concentration–time curve from time zero to infinity (AUC) and maximum (peak) plasma drug concentration (Cmax) (67% and 63% decrease, respectively) was observed with the P-gp probe substrate fexofenadine. Lorlatinib coadministration also decreased the AUC and Cmax of bupropion (CYP2B6 probe substrate) by 25% and 27%, tolbutamide (CYP2C9 probe substrate) by 43% and 15%, and acetaminophen (UGT probe substrate) by 45% and 28%, respectively. Conclusions: Lorlatinib is a net moderate inducer of P-gp and a weak inducer of CYP2B6, CYP2C9, and UGT after steady state is achieved with daily dosing. Medications that are P-gp substrates with a narrow therapeutic window should be avoided in patients taking lorlatinib; no dose modifications are needed with substrates of CYP2B6, CYP2C9, or UGT. ClinicalTrials.gov: NCT01970865.

Original languageEnglish
Pages (from-to)171-182
Number of pages12
JournalClinical Pharmacokinetics
Volume63
Issue number2
DOIs
StatePublished - Feb 2024

Keywords

  • Humans
  • Carcinoma, Non-Small-Cell Lung/drug therapy
  • Cytochrome P-450 CYP2C9/genetics
  • Lung Neoplasms/drug therapy
  • Cytochrome P-450 CYP2B6
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Uridine
  • Glucuronosyltransferase/genetics
  • Drug Interactions
  • Lactams, Macrocyclic/adverse effects
  • Aminopyridines
  • Lactams
  • Pyrazoles

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