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

Chen, J; Bearz, A; Kim, DW; Mamdani, H; Bauman, J; Chiari, R; Ou, SI; Solomon, BJ; Soo, RA; Felip, E; Shaw, AT; Thurm, H; Clancy, JS; Lee, K; O&#39;Gorman, M; Tanski, C; Pithavala, YK

Author(s): Chen, J; Bearz, A; Kim, DW; Mamdani, H; Bauman, J; Chiari, R; Ou, SI; Solomon, BJ; Soo, RA; Felip, E; Shaw, AT; Thurm, H; Clancy, JS; Lee, K; O'Gorman, M; Tanski, C; Pithavala, YK;
Details: Publication Year 2024-02,Volume 63,Issue #2,Page 171-182
Journal Title: Clinical Pharmacokinetics
Publication Type: Research article
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 (C(max)) (67% and 63% decrease, respectively) was observed with the P-gp probe substrate fexofenadine. Lorlatinib coadministration also decreased the AUC(∞) and C(max) 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.
Publisher: Springer Nature
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
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1007/s40262-023-01309-4
Open Access at Publisher's Site: https://doi.org/10.1007/s40262-023-01309-4
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-03-05 04:47:26

Last Modified: 2024-03-05 04:47:58