Pharmacokinetic-Based Drug–Drug Interactions with Anaplastic Lymphoma Kinase Inhibitors: A Review

Figures & data

Table 1 PK Parameters for ALK-TKIs

PK	Absorption		Distribution		Metabolism	T1/2 (h)	CL/F (L/h)	Excretion
	Tmax (h)	F (%)	Vd/Vss (L)	PB (%)	Enzymes			Feces (%)	Urine (%)
Crizotinib^Citation11,Citation12	4–6^a	43	1772*	91	CYP3A	42^a	100^a 60^b	63	22
Ceritinib^Citation14,Citation15	4–6^a	NK	4230	97	CYP3A	41^a	88.5^a 33.2^b	92	1.3
Alectinib^Citation17,Citation18	4^b	37	475*	>99	CYP3A4	33	81.9	98	<0.5
Brigatinib^Citation19,Citation20	1–4^a	NK	153*	91	CYP3A4 CYP2C8	25^b	12.7^b	65	25
Lorlatinib^Citation21,Citation22	1.2^a 2^b	81	305*	66	CYP3A4 UGT1A4	24^a	11^a 18^b	41	48
Entrectinib	4–6^a	>50	551	>99	CYP3A4	20	19.6	83	3

Notes: T_max, time to achieve C_max; V_d, apparent volume of distribution; PB, Plasma protein binding; T_1/2, elimination half-life; CL/F, apparent clearance; F, absolute bioavailability; NK, not known. *Steady state volume of distribution (V_ss), ^aSingle dose administrations, ^bMultiple dose administrations at steady state.

Table 2 Effect of ARAs on the Absorption of ALK-TKIs

Drug	Condition	Mean Change		Clinically Significant	Recommendations
		AUCR	CmaxR
Crizotinib^Citation13	Esomeprazole 40 mg once daily for 5 days	0.9	1.0	No	Dose adjustment is not required for coadministration of crizotinib with ARAs
Ceritinib^Citation16,Citation31	Esomeprazole 40 mg once daily for 6 days	0.24 (healthy subjects)	0.21 (healthy subjects)	No	Dose adjustment is not required when ceritinib is co-administered with ARAs
		0.70 (patients)	0.75 (patients)
		0.98 (at steady state)	0.93 (at steady state)
Alectinib^Citation19,Citation33	Esomeprazole 40 mg once daily for 6 days	1.22 (alectinib) 1.10 (M4) 1.17 (alectinib+M4)	1.16 (alectinib) 1.02 (M4) 1.13 (alectinib+M4)	No	Dose adjustment is not required for coadministration of alectinib with ARAs
Brigatinib^Citation20,Citation21	No studies	No data	No data	No	Dose adjustment is not required for coadministration of brigatinib with ARAs
Lorlatinib^Citation36	Rabeprazole 20 mg once daily for 5 days	1.01	0.71	No	Dose adjustment is not required for coadministration of lorlatinib with ARAs
Entrectinib^Citation24,Citation25	Lansoprazole 30 mg once daily	0.75 (entrectinib) 0.84 (M5)	0.77 (entrectinib) 0.83 (M5)	No	Dose adjustment is not required for coadministration of entrectinib with ARAs

Notes: C_maxR and AUCR are mean C_max and AUC ratios when the substrate was given with/without a perpetrator.

Table 3 Effects of Food on the Absorption of ALK-TKIs

Drugs	BCS	Design	Condition	Mean Change		Clinically Significant	Recommendations
				AUCR	CmaxR
Crizotinib^Citation12,Citation39	4	250 mg single dose	High-fat meal	0.86	0.86	No	Taken with or without food
Ceritinib^Citation15,Citation40,Citation41	4	500 mg single dose	High-fat meal	1.73	1.41	Yes	Taken with food
			Low-fat meal	1.58	1.43
		750 mg single dose	High-fat meal	1.64	1.58
			Low-fat meal	1.39	1.42
		450 mg multiple dose	Low-fat meal	Similar with 750 mg daily under fasted conditions
Alectinib^Citation18,Citation32,Citation42	4	600 mg single dose	High-fat meal	2.92 (alectinib) 3.28 (M4) 3.11 (alectinib+M4)	2.70 (alectinib) 3.77 (M4) 3.31 (alectinib+M4)	Yes	Taken with food
Brigatinib^Citation20,Citation43	1	180 mg single dose	High-fat meal	0.98	0.87	No	Taken with or without food
Lorlatinib^Citation22,Citation36	4	100 mg single dose	High-fat meal	1.05	0.91	No	Taken with or without food
Entrectinib^Citation24,Citation25	2	600 mg single dose	High-fat meal	1.15 (entrectinib) 1.0 (M5)	1.06 (entrectinib) 1.0 (M5)	No	Taken with or without food

Table 4 The Potential DDIs Between Drug Transporters and ALK-TKIs

Drugs	Substrates	Recommendations
Crizotinib^Citation12,Citation13,Citation48	P-gp, OATP1B1/3, OATP2B1, OCT2	NA
Ceritinib^Citation15,Citation16	P-gp (major), BCRP (weak)	EMA: Caution is advised when concomitant use of P-gp inhibitors and inducers.
Alectinib^Citation18,Citation19,Citation57	NA	EMA: Clinically relevant DDIs with P-gp inhibitors and inducers are not likely to happen.
Brigatinib^Citation20,Citation21	P-gp, BCRP	FDA/EMA: No dose adjustment is required for brigatinib during coadministration with P-gp and BCRP inhibitors.
Lorlatinib^Citation22,Citation23	NA	EMA: Clinically relevant DDIs with P-gp and BCRP inhibitors or inducers are not likely to appear.
Entrectinib^Citation24	NA	NA

Abbreviation: NA, not applicable/not available.

Table 5 The Potential DDIs Between ALK-TKIs and Other Transporter Substrates

Drugs	Inhibitor	Recommendations
Crizotinib^Citation12,Citation13,Citation49,Citation50	P-gp, OCT1/2, OATP1B1/3, OATP2B1, OATP4C1, MATE1, MATE2-K	EMA: Close clinical surveillance is recommended when using these substrates.
Ceritinib^Citation15,Citation16,Citation56,Citation57	P-gp, BCRP, OATP1B1/3, OAT1, OCT2	EMA: Caution should be exercised with concomitant use of these substrates.
Alectinib^Citation18,Citation19,Citation59	P-gp, BCRP, BSEP	EMA: Appropriate monitoring is recommended when co-administered with these substrates.
Brigatinib^Citation20,Citation21	P-gp, BCRP, OCT1, MATE1, MATE2-K	EMA: Patients should be closely monitored when concomitant use of these substrates with a narrow therapeutic index.
Lorlatinib^Citation22,Citation23	P-gp, OCT1, OAT3, MATE1, OATP1B1/3, BCRP	NA
Entrectinib^Citation24	P-gp, BCRP, OATP1B1, and MATE1	NDA: Dose adjustment for P‐gp substrates when co-administered with entrectinib is not needed.

Abbreviation: NA, not applicable/not available.

Table 6 Effects of CYP Inhibitors and Inducers on the Exposure of ALK-TKIs

Drugs	CYP Enzymes		Mean Change		Clinically Significant	Recommendations
	Inhibitors	Inducers	AUCR	CmaxR
Crizotinib^Citation12,Citation13,Citation67,Citation68,	Ketoconazole		3.16	1.44	Yes	Avoiding concomitant use of strong CYP3A inhibitors, if concomitant use of is unavoidable, reduce the dose of crizotinib to 250 mg once daily.
	Itraconazole		1.57	1.33	Yes
	Diltiazem/Verapamil		1.17	NK	NK	Caution is recommended when concomitant use of moderate CYP3A inhibitors.
		Rifampin	0.16	0.21	Yes	Avoiding concomitant use of strong CYP3A inducers.
Ceritinib^Citation15,Citation16,Citation30	Ketoconazole fluconazole		2.89 1.37	1.22 1.32	Yes No	Avoiding concomitant use of strong CYP3A inhibitors, if concomitant use is unavoidable, reduce the dose by approximately one third.
		Rifampin efavirenz	0.30 0.57	0.56 0.61	Yes No	Avoiding concomitant use of strong CYP3A inducers.
Alectinib^Citation19,Citation32,Citation71	Posaconazole		1.75 (alectinib) 0.75 (M4) 1.36 (alectinib+M4)	1.18 (alectinib) 0.29 (M4) 0.93 (alectinib+M4)	No	No dose adjustments are required when alectinib is co-administered with CYP3A inhibitors or inducers.
		Rifampin	0.27 (alectinib) 1.79 (M4) 0.82 (alectinib+M4)	0.49 (alectinib) 2.20 (M4) 0.96 (alectinib+M4)	No
Brigatinib^Citation72,Citation73	Itraconazole		2.01	1.21	Yes	Avoiding coadministration of strong CYP3A inhibitors, if coadministration is unavoidable, reduce the brigatinib once daily dose by approximately 50%.
	Diltiazem/Verapamil		1.32 1.40	1.08 1.08	Yes	Avoiding coadministration of moderate CYP3A inhibitors, if coadministration is unavoidable, reduce the brigatinib once daily dose by approximately 40%.
	Gemfibrozil		0.88	0.59	No	No dose adjustments are required when brigatinib is co-administered with CYP2C8 inhibitors
		Rifampin	0.20	0.40	Yes	Avoiding coadministration of strong or moderate CYP3A inducers, if coadministration is unavoidable, increase the brigatinib once daily dose in 30 mg increments after 7 days of treatment, up to a maximum of twice the brigatinib dose.
		Efavirenz	0.52	0.85	Yes
Lorlatinib^Citation22,Citation23	Itraconazole		1.42	1.24	Yes	Avoiding coadministration of strong CYP3A inhibitors, if concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg, and from 75 mg to 50 mg if adverse reactions occurred.
		Rifampin	0.15	0.24	Yes	Avoiding coadministration of strong CYP3A inducers.
Entrectinib^Citation24,Citation25	Itraconazole		6.04 (entrectinib) 2.52 (M5)	1.73 (entrectinib) 0.62 (M5)	Yes	For adults and pediatric patients 12 years and older with BSA greater than 1.5 m^2, coadministration of entrectinib with moderate or strong CYP3A inhibitors should be avoided, if coadministration cannot be avoided, entrectinib 100 mg qd is recommended for strong CYP3A4 inhibitors, and 200 mg qd for moderate CYP3A4 inhibitors. For pediatric patients 12 years and older with BSA less than or equal to 1.5 m^2, Avoiding coadministration of moderate or strong CYP3A inhibitors
	Erythromycin		3.40 (entrectinib) 2.08 (M5)	2.89 (entrectinib) 1.21 (M5)	Yes
		Rifampin	0.23 (entrectinib) 0.13 (M5)	0.44 (entrectinib) 0.25 (M5)	Yes	Avoiding coadministration of moderate or strong CYP3A inducers.
		Efavirenz	0.44 (entrectinib) 0.53 (M5)	0.57 (entrectinib) 0.72 (M5)	Yes

Table 7 Effects of ALK-TKIs on the Exposure of Other Drugs

Drugs	CYP Substrates	Change of CYP Substrates		Clinically Significant	Recommendations
		AUCR	CmaxR
Crizotinib^Citation13,Citation69	Midazolam	3.65	2.02	Yes	Avoiding concomitant use of crizotinib with CYP3A substrates. If concomitant use is unavoidable, reduce the dose of CYP3A substrates.
Ceritinib^Citation15,Citation30	Midazolam	5.40	1.80	Yes	Avoiding coadministration of ceritinib with sensitive CYP3A and CYP2C9 substrates. If concomitant use is unavoidable, consider dose reduction of the CYP3A and CYP2C9 substrates.
	Warfarin	1.54	1.0	Yes
Alectinib^Citation18,Citation19,Citation32	Midazolam	0.97	0.92	No	No dose adjustments are required when alectinib is co-administered with CYP3A substrates.
Brigatinib^Citation20,Citation21	NA	NA	NA	NK	Coadministration of brigatinib with CYP3A substrates with a narrow therapeutic index should be avoided.
Lorlatinib^Citation22,Citation23	Midazolam	0.36	0.50	Yes	Avoiding concomitant use of lorlatinib with CYP3A substrates.
Entrectinib^Citation24,Citation25	Midazolam	1.50	0.79	No	Dose adjustment is not needed for sensitive CYP3A substrates when coadministered with entrectinib.

Abbreviations: NK, not known; NA, not applicable/not available.

Table 8 The Effect of RI and HI on the Exposure of ALK-TKIs

Drugs	RI		Recommendations	HI		Recommendations
	AUCR	Cmax R		AUCR	Cmax R
Crizotinib^Citation12,Citation13,Citation79,Citation80	Mild and moderate RI: Similar with NRF.		Mild and moderate RI: Dose adjustment is not needed. Severe RI: 250 mg once daily.	0,91 (mild)	0.91 (mild)	Mild HI: Dose adjustment is not needed. Moderate HI: 200 mg twice daily. Severe HI: 250 mg once daily.
				1.50 (moderate)	1.44 (moderate)
	0.21 (severe)	0.66 (severe)		0.65 (severe)	0.73 (severe)
Ceritinib^Citation16,Citation30	1.09 (mild) 1.19 (moderate)	NK	Mild and moderate RI: Dose adjustment is not needed. Severe RI: No information is available.	1.18 (mild) 1.02 (moderate) 1.66 (severe)	NK	Mild and moderate HI: Dose adjustment is not needed. Severe HI: 300 mg once daily.
Alectinib^Citation18,Citation81	Mild and moderate RI: Similar with NRF Severe RI: Not studied		Mild and moderate RI: Dose adjustment is not needed. Severe RI: Withhold alectinib.	Alectinib+M4 1.36 (moderate) 1.76 (severe)	Alectinib+M4 1.16 (moderate) 0.98 (severe)	Mild and moderate HI: Dose adjustment is not needed. Severe HI: 450 mg twice daily.
Brigatinib^Citation20,Citation21	Mild and moderate RI: Similar with NRF. Severe RI: 1.94	NK	Mild and moderate RI: Dose adjustment is not needed. Severe RI: Reduce the alectinib once daily by 50%.	Mild and moderate HI: Similar with NHF. Severe HI: 1.37	NK	Mild and moderate HI: Dose adjustment is not needed. Severe HI: Reduce the alectinib once daily by 40%.
Lorlatinib^Citation22	Mild and moderate RI: Similar with NRF. Severe RI: Not studied.		Mild and moderate RI: Dose adjustment is not needed. Severe RI: No information is available.	Mild HI: Similar with NHF. Moderate and severe HI: Not studied.		Mild HI: Dose adjustment is not needed. Moderate and severe HI: No information is available.
Entrectinib^Citation24	Mild and moderate RI: Similar with NRF. Severe RI: Not studied.		Mild and moderate RI: Dose adjustment is not needed. Severe RI: No information is available.	Mild HI: Similar with NHF. Moderate and severe HI: Not studied.		Mild HI: Dose adjustment is not needed. Moderate and severe HI: No information is available.

Abbreviations: NRF, normal renal function; NHF, normal hepatic function; NK, not known.

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