Evaluation of the Effect of Lorlatinib on CYP2B6, CYP2C9, UGT, and P-Glycoprotein Substrates in Patients with Advanced Non-Small Cell Lung Cancer.
Journal
Clinical pharmacokinetics
ISSN: 1179-1926
Titre abrégé: Clin Pharmacokinet
Pays: Switzerland
ID NLM: 7606849
Informations de publication
Date de publication:
11 Dec 2023
11 Dec 2023
Historique:
accepted:
12
09
2023
medline:
11
12
2023
pubmed:
11
12
2023
entrez:
11
12
2023
Statut:
aheadofprint
Résumé
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. 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. 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 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. gov: NCT01970865.
Sections du résumé
BACKGROUND AND OBJECTIVE
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
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
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
CONCLUSIONS
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
RESULTS
gov: NCT01970865.
Identifiants
pubmed: 38079095
doi: 10.1007/s40262-023-01309-4
pii: 10.1007/s40262-023-01309-4
doi:
Banques de données
ClinicalTrials.gov
['NCT01970865']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023. The Author(s).
Références
Johnson TW, Richardson PF, Bailey S, Brooun A, Burke BJ, Collins MR, et al. Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(m etheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations. J Med Chem. 2014;57(11):4720–44.
doi: 10.1021/jm500261q
pubmed: 24819116
Shaw AT, Felip E, Bauer TM, Besse B, Navarro A, Postel-Vinay S, et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 2017;18(12):1590–9.
doi: 10.1016/S1470-2045(17)30680-0
pubmed: 29074098
pmcid: 5777233
Solomon BJ, Besse B, Bauer TM, Felip E, Soo RA, Camidge DR, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018;19(12):1654–67.
doi: 10.1016/S1470-2045(18)30649-1
pubmed: 30413378
Shaw AT, Bauer TM, de Marinis F, Felip E, Goto Y, Liu G, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med. 2020;383(21):2018–29.
doi: 10.1056/NEJMoa2027187
pubmed: 33207094
Pfizer Inc. LORBRENA
European Medicines Agency. Lorviqua (lorlatinib). 2021 [cited 2021 December 1]. https://www.ema.europa.eu/en/medicines/human/EPAR/lorviqua .
Shaw AT, Solomon BJ, Besse B, Bauer TM, Lin CC, Soo RA, et al. ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer. J Clin Oncol. 2019;37(16):1370–9.
doi: 10.1200/JCO.18.02236
pubmed: 30892989
pmcid: 6544460
Chen J, O’Gorman MT, James LP, Klamerus KJ, Mugundu G, Pithavala YK. Pharmacokinetics of lorlatinib after single and multiple dosing in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer: results from a global phase I/II study. Clin Pharmacokinet. 2021;60(10):1313–24.
doi: 10.1007/s40262-021-01015-z
pubmed: 33937954
pmcid: 8505377
Willson TM, Kliewer SA. PXR, CAR and drug metabolism. Nat Rev Drug Discov. 2002;1(4):259–66.
doi: 10.1038/nrd753
pubmed: 12120277
Chen J, Xu H, Pawlak S, James LP, Peltz G, Lee K, et al. 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;37(2):745–58.
doi: 10.1007/s12325-019-01198-9
pubmed: 31863284
Wang YM, Ong SS, Chai SC, Chen T. Role of CAR and PXR in xenobiotic sensing and metabolism. Expert Opin Drug Metab Toxicol. 2012;8(7):803–17.
doi: 10.1517/17425255.2012.685237
pubmed: 22554043
pmcid: 3593589
Li W, Sparidans RW, Wang Y, Lebre MC, Wagenaar E, Beijnen JH, et al. P-glycoprotein (MDR1/ABCB1) restricts brain accumulation and cytochrome P450–3A (CYP3A) limits oral availability of the novel ALK/ROS1 inhibitor lorlatinib. Int J Cancer. 2018;143(8):2029–38.
doi: 10.1002/ijc.31582
pubmed: 29744867
Verschraagen M, Koks CH, Schellens JH, Beijnen JH. P-glycoprotein system as a determinant of drug interactions: the case of digoxin-verapamil. Pharmacol Res. 1999;40(4):301–6.
doi: 10.1006/phrs.1999.0535
pubmed: 10527640
US Food and Drug Administration (FDA). Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers. 2023 [cited 2023 April 26]. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table2-1 .
Kiang TK, Ensom MH, Chang TK. UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacol Ther. 2005;106(1):97–132.
doi: 10.1016/j.pharmthera.2004.10.013
pubmed: 15781124
Shaw AT, Solomon BJ, Chiari R, Riely GJ, Besse B, Soo RA, et al. Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1–2 trial. Lancet Oncol. 2019;20(12):1691–701.
doi: 10.1016/S1470-2045(19)30655-2
pubmed: 31669155
Chen J, O’Gorman MT, James LP, Klamerus KJ, Mugundu G, Pithavala YK. Pharmacokinetics of lorlatinib after single and multiple dosing in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer: results from a global phase I/II study. Clin Pharmacokinet. 2021;60(10):1313–24.
doi: 10.1007/s40262-021-01015-z
pubmed: 33937954
pmcid: 8505377
Wellbutrin. Package insert. GlaxoSmithKline. 2019.
Miners JO, Birkett DJ. Use of tolbutamide as a substrate probe for human hepatic cytochrome P450 2C9. Methods Enzymol. 1996;272:139–45.
doi: 10.1016/S0076-6879(96)72017-7
pubmed: 8791771
Prescott LF. Kinetics and metabolism of paracetamol and phenacetin. Br J Clin Pharmacol. 1980;10(Suppl 2):291S-S298.
pubmed: 7002186
pmcid: 1430174
Hamman MA, Bruce MA, Haehner-Daniels BD, Hall SD. The effect of rifampin administration on the disposition of fexofenadine. Clin Pharmacol Ther. 2001;69(3):114–21.
doi: 10.1067/mcp.2001.113697
pubmed: 11240975
US Food and Drug Administration (FDA). Guidance for Industry. Clinical Drug Interaction Studies—Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) January 2020 Clinical Pharmacology.
Ford SL, Sutton K, Lou Y, Zhang Z, Tenorio A, Trezza C, et al. Effect of rifampin on the single-dose pharmacokinetics of oral cabotegravir in healthy subjects. Antimicrob Agents Chemother. 2017;61(10):1128.
doi: 10.1128/AAC.00487-17
Jefferson JW, Pradko JF, Muir KT. Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations. Clin Ther. 2005;27(11):1685–95.
doi: 10.1016/j.clinthera.2005.11.011
pubmed: 16368442
Patel M, Chen J, McGrory S, O’Gorman M, Nepal S, Ginman K, et al. The effect of itraconazole on the pharmacokinetics of lorlatinib: results of a phase I, open-label, crossover study in healthy participants. Invest New Drugs. 2020;38(1):131–9.
doi: 10.1007/s10637-019-00872-7
pubmed: 31728714
Li J, Pithavala YK, Gong J, LaBadie RR, Mfopou JK, Chen J. The effect of modafinil on the safety and pharmacokinetics of lorlatinib: a phase I study in healthy participants. Clin Pharmacokinet. 2021;60(10):1303–12.
doi: 10.1007/s40262-021-01026-w
pubmed: 33937953
pmcid: 8505275
Bénit CP, Vecht CJ. Seizures and cancer: drug interactions of anticonvulsants with chemotherapeutic agents, tyrosine kinase inhibitors and glucocorticoids. Neuro-Oncology Pract. 2015;3(4):245–60.
doi: 10.1093/nop/npv038
Lutz JD, Kirby BJ, Wang L, Song Q, Ling J, Massetto B, et al. Cytochrome P450 3A induction predicts P-glycoprotein induction; part 1: establishing induction relationships using ascending dose rifampin. Clin Pharmacol Ther. 2018;104(6):1182–90.
doi: 10.1002/cpt.1073
pubmed: 29569723
pmcid: 6282691
Kliewer SA, Goodwin B, Willson TM. The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr Rev. 2002;23(5):687–702.
doi: 10.1210/er.2001-0038
pubmed: 12372848
Matsuyama T, Tachi T, Katsuno H, Sugioka M, Aoyama S, Osawa T, et al. Effects of polypharmacy on the prevalence of adverse drug events resulting in outpatient visits and hospitalization. Pharmazie. 2021;76(6):279–86.
pubmed: 34078523
Wessler JD, Grip LT, Mendell J, Giugliano RP. The P-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol. 2013;61(25):2495–502.
doi: 10.1016/j.jacc.2013.02.058
pubmed: 23563132