Table IV.

DDI between ALK-TKIs and inhibitors/inducers of CYP.

Drug	DDI	Mechanism	Consequences	Current recommendations
Crizotinib	Ketoconazole	CYP3A4 inhibitor	AUCinf augmentation of crizotinib with ketoconazole 3.2-fold	CYP3A4 inhibitors or inducers significantly affect the pharmacokinetics of crizotinib after single- and multiple-dose administration
	Rifampin	CYP3A4 inducer	AUCinf diminution of crizotinib with rifampin 82%
	Midazolam	CYP3A4 inhibitor	It can increase midazolam plasma AUC by 3.7-fold
Ceritinib	PPI	P-gp inhibitor	Augmentation of ceritinib with ketoconazole Cmax by 22% and AUC by 186%	The drug label of ceritinib warns against the co-administration of strong CYP3A inhibitors. It is preferable to avoid the co-administration of strong CYP3A inducers
	Warfarin	Strong CYP3A inhibitor
	Midazolam	Strong CYP3A inhibitor
Brigatinib	Rifampin	Strong CYP3A inducer	The co-administration of rifampin decreases the AUCinf of ceritinib by 70%
	Itraconazole	CYP3A inducer	Augmentation of ceritinib with itraconazole Cmax by 21% and AUC by 101%
	Ketoconazole	Strong CYP3A inhibitor
	Gemfibrozil	Strong CYP2C8 inhibitor	Diminution of brigatinib with gemfibrozil AUC and Cmax by 12% and 41%, respectively.	The effects of gemfibrozil on the pharmacokinetics of brigatinib are not clinically significant; however, the concomi tant use of brigatinib with strong CYP3A inhibitors needs to be avoided
	Rifampin	CYP 3A4 inducer	Rifampin decreases brigatinib Cmax and AUCinf by 60% and 80%, respectively	The co-administration of strong CYP3A inducers with brigatinib needs to be avoided
Alectinib	Posaconazole	CYP 3A4 inhibitor
	Esomeprazole	CYP 3A4 inhibitor
	Rifampin	CYP 3A4 inhibitor	Diminution of alectinib and M4 with rifampin AUC and Cmax by 26.8% and 48.6% and 220% and 179%, respectively
	Midazolam	CYP 3A4 substrate	Alectinib does not affect midazolam exposure
Lorlatinib	Rifampin	CYP 3A4 inducer	UK	UK

ALK-TKIs, anaplastic lymphoma kinase tyrosine kinase inhibitors; AUC, area under the curve; AUC_inf, AUC from zero to infinity; C_max, maximum plasma concentration; CYP, Cytochrome P450; CYP 3A4, Cytochrome P450 3A4; DDI, drug-drug interaction; P-gp, P-glycoprotein; PPI, Proton-pump inhibitor; UK, unknown.