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. 2024 Feb;63(2):171-182.
doi: 10.1007/s40262-023-01309-4. Epub 2023 Dec 11.

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  1   2 , Alessandra Bearz  3 , Dong-Wan Kim  4 , Hirva Mamdani  5 , Jessica Bauman  6 , Rita Chiari  7 , Sai-Hong Ignatius Ou  8 , Benjamin J Solomon  9 , Ross A Soo  10 , Enriqueta Felip  11 , Alice T Shaw  12 , Holger Thurm  13 , Jill S Clancy  14 , Kimberly Lee  15 , Melissa O'Gorman  15 , Cherie Tanski  15 , Yazdi K Pithavala  16
Affiliations

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 et al. Clin Pharmacokinet. 2024 Feb.

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.

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Conflict of interest statement

JC was employed by Pfizer at the time of the work, owns stocks in Pfizer, and is currently employed by Roche/Genentech. AB reports advisory board fees from AstraZeneca, Bristol Myers Squibb, Pfizer, and Roche; speaker fees from Eli Lilly, Pfizer, and Roche. D-WK reports administrative support and grants from Amgen, AstraZeneca, Boehringer Ingelheim, Bridge BioTherapeutics, Chong Keun Dang, Daiichi Sankyo, GlaxoSmithKline, Janssen, Merck, Merus, MSD, Novartis, Pfizer, Roche, Takeda, and Yuhan; grants from Alpha Biopharma, Hanmi, InnoN, Mirati Therapeutics, ONO Pharmaceutical, Turning Point Therapeutics, and Xcovery. HM reports advisory board fees from AstraZeneca, Genentech, and Zentalis; received a grant from U CAN-CER VIVE Foundation; and received institutional research funding from Pfizer. JB reports consulting fees or honoraria from BeiGene, Blueprint Medicines, Eli Lilly, Janssen, Merck, Mirati, Pfizer, and Turning Point Therapeutics. RC declares no conflicts of interest. S-HIO reports consulting fees or honorarium from AnHeart Therapeutics, BeiGene, Daiichi Sankyo, Eli Lilly, Johnson and Johnson/Janssen, and Pfizer; speaker fees from DAVA Oncology, Johnson and Johnson/Janssen, and Pfizer; advisory board fees from Elevation Oncology; stocks in Elevation Oncology and Turning Point Therapeutics. BJS reports advisory board fees or honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Merck, Pfizer, Roche/Genentech; and received fees from BeiGene, Janssen, Novartis, and Takeda. RAS reports advisory board fees or honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, EMD Serono, J INTS BIO, Janssen, Merck, Microquin, Novartis, Pfizer, Puma Biotechnology, Roche, Taiho, Takeda, ThermoFisher, and Yuhan; and research grants from AstraZeneca and Boehringer Ingelheim. EF reports consulting fees or honoraria from Amgen, AstraZeneca, BerGenBio, Bristol Myers Squibb, Daichi Sankyo, Eli Lilly, F. Hoffman-La Roche, GlaxoSmithKline, Janssen, Merck Serono, MSD, Novartis, Peptomyc, Pfizer, Sanofi, and Takeda; speaker fees from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffman-La Roche, Janssen, Medical Trends, MedScape, MSD, Novartis, PeerVoice, Pfizer, Sanofi, Takeda, and Touch Oncology; and is an independent member of the board at Grifols. AS is employed by and owns stock in Novartis. HT, JSC, KL, MO, CT, and YKP are employed by and own stocks in Pfizer.

Figures

Fig. 1
Fig. 1
Median plasma concentration–time profiles of a bupropion following single oral doses of bupropion alone and with once-daily lorlatinib, b tolbutamide following single oral doses of tolbutamide alone and with once-daily lorlatinib, c acetaminophen following single oral doses of acetaminophen alone and with once-daily lorlatinib, and d fexofenadine following single oral doses of fexofenadine alone and with once-daily lorlatinib
Fig. 2
Fig. 2
Forest plot illustrating the effect of daily dosing of lorlatinib on the pharmacokinetic parameters (fold change and 90% CI of the ratios of adjusted geometric means for Cmax and AUC∞) of probe substates used in this study. Adjusted geometric mean ratio refers to the estimate from the ANOVA model using a mixed effect model with treatment as a fixed effect and subject as a random effect. ANOVA analysis of variance, AUC∞/AUCinf area under the plasma concentration–time curve from time zero to infinity, CI confidence interval, Cmax maximum (peak) plasma drug concentration, CYP cytochrome P450, P-gp P-glycoprotein, UGT uridine 5′-diphospho-glucuronosyltransferase
See this image and copyright information in PMC

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