. 2015 Oct 11;3(4):245–260. doi: 10.1093/nop/npv038

Table 5.

Influence of interfering antiepileptic drug (AED) on affecting activity of tyrosine kinase inhibitors and other targeted agents

Tyrosine Kinase Inhibitor	Mechanism (Target)	AED and Dose	Involved CYPs/UGTs			No of Patients	Dose at MTD	Change in CTD Activity	Factor of Change of Metab	Reference
Tyrosine Kinase Inhibitor	Mechanism (Target)	AED and Dose	Substrate	Inducer	Inhibitor	No of Patients	Dose at MTD	Change in CTD Activity	Factor of Change of Metab	Reference
Bortezomib	Proteasome inhibitor	EIAEDS	CYP3A (2C19)			3	nEI + TMZ 1.3 mg/m² EI + TMZ ?	Cl ↑ AUC ↓	2.75 0.54	Portnow, 2012⁶³
Crizotinib	ALK/MET/ROS1 inhibitor	Midazolam	CYP3A4 (1A9, 2D6, 2C19)	CYP2B6, 2C8, 2C9, UGT	CYP3A4			AUC ↑	3.7	Mao, 2013⁶⁴
Dasatinb	SCR, Bcr-Abl,	EIAEDs	CYP3A (2C8, UGT)		CYP3A4, 2C8, 1A1			AUC ↓	0.45	Reardon, 2012⁶⁵
Enzastaurin	PI3 K/AKT	EIAEDs	CYP3A (2C19)			15	nEI 525 mg	Cl ↑ AUC ↓	6.96 0.21	Kreisl, 2010⁶⁶
Erlotinib	EGFR	EIAEDs Midazolam	CYP3A (1A1, 1A2, 2C8, 2D6)	CYP3A4		90 110	nEI + TMZ 150 mg/d nEI 200 mg/d EI + TMZ 450 mg/d EI 500 mg/d	AUC ↓ AUC ↓	0.45–0.63 0.76	Prados, 2006⁹² Vd Bent, 2009⁶⁷ Shao, 2014⁶⁸
Gefitinib	EGFR	EIAEDs	CYP3A, 2D6 (1A1, 2C19)		2C19, 2D6	68 30	nEI + TMZ 250 mg/d EI + TMZ 1000 mg/d	Cl ↑ T 1/2 ↓ AUC ↓	2.27–3.42 0.84 0.31–0.71	Reardon, 2006⁶⁹ Prados, 2008⁷⁰
Imatinib	Bcr-Abl, c-kit, PDGFR	EIAEDs Levetiracetam Valproic acid Lamotrigine Phenytoin Carbamazepine Oxcarbazepine Topiramate	CYP3A (2C9, 2D6)	3A4, 2C8	3A4/5, 2C9, 2D6	33	nEI 1200 mg/d EI 1200 mg/d nEI + TMZ 1000 mg/d EI + TMZ 1000 mg/d	Cl ↑ T 1/2 ↓ AUC ↓ Cl ↑ T 1/2 ↓ AUC ↓ Through Plasma levels	3.42–4.13 0.30–0.60 0.26–0.79 1.30 0.39 0.76 0.97 1.02 1.01 0.31 0.29 0.45 0.58	Reardon, 2008⁷¹ Wen, 2006⁷² Pursche, 2008⁷³
Lapatinib	EGFR, HER2	CBZ Midazolam	CYP3A (1A2, 2C8, 2C9, 2C19, 2D6)		3A4, 2C8	16 24	EI 1000 mg	Cl ↑ T 1/2 ↓ AUC ↓ AUC ↑	8.83 0.28 0.27–0.28 1.4	Smith, 2009⁷⁵ Thiessen, 2010⁷⁴ Shao, 2014⁶⁸
Pazopanib	c-kit, FGFR, PDGFR, VEGFR1–3	EIAEDs Midazolam	CYP3A (1A2, 2C8)	3A4	CYP3A4, 2D6 2B6, 2C9, 2C19	75		AUC ↓ AUC ↑	∼0.5 1.35	Reardon, 2013⁷⁶ Shao, 2014⁶⁸
Evorolimus	mTOR	EIAEDs	CYP3A (2C19)			32		AUC ↓	0.48	Mason, 2012⁷⁷
Sirolimus	mTOR	EIAEDs	CYP3A (2C19)			23 25 36		T 1/2 ↓ AUC ↓	0.46–0.75 0.54–0.62	Boni, 2007⁷⁸ Kuhn, 2007⁷⁹ Galanis, 2011⁸⁰
Temsirolimus	mTOR	EIAEDs Valproic acid	CYP3A (2C19)			25 36 8	nEI 170 mg/d EI 250 mg/d	Cl ↑ T 1/2 = AUC ↓ C max	1.20–1.47 0.66–0.85 ∼ 2	Boni, 2007⁷⁸ Kuhn, 2007⁷⁹ Galanis, 2005⁸⁰ Coulter, 2013⁸¹
Sorafenib	c-kit, PDGFR, RAF, VEGFR1-3	EIAEDs Midazolam	CYP3A, UGT1A9		CYP3A4, 2B6, 2C8, 2C9, 2D6, UGT1A1, 1A9	32		T1/2 ↓ AUC ↓ AUC ↓	0.39–0.56 0.36–0.49 0.85	Reardon, 2011⁸² Flaherty, 2011⁸³
Sunitinib	PDGFR, VEGFR, c-KIT	EIAEDs	CYP3A (2C19)							Widmer, 2014⁸⁶ Bilbao, 2015⁸⁴
Tamoxifen	Estrogene receptor	Phenytoin	CYP3A (2C19)			1		Dose ↓	0.46	Gryn, 2014⁸⁵
Tipifarnib	Ras, Farnesyl-TF inhibitor	EIAEDs	CYP3A (2C19)				nEI 300 mg bid EI 600 mg bid	Cl ↑ T 1/2 = AUC ↓	2.90 = 0.52	Cloughesy, 2005⁸⁷
Vandetanib	EGFR, RET, VEGFR2	EIAEDS	CYP3A		CYP2D6	79		Cl = T 1/2 = AUC =		Kreisl, 2012⁸⁸
Vatalanib	C-kit, PDFGR VEGFR1-3	EIAEDs	CYP3A (2C19)			10	nEI 1000 mg bid EI 1000 mg bid	Cl ↑ T 1/2 = AUC ↓	2.68–3.09 0.42–0.82	Reardon, 2009⁸⁹ Gerstner, 2011⁹⁰
Vemurafenib	V600E BRAF kinase		CYP3A4	CYP3A4	CYP1A2, 2D6					Da Rocha Dias, 2013⁹¹

Abbreviations: bid, bis in die; CBZ, carbamazepine; EIAEDs, enzyme-inducing anti-epileptic drugs; PB, phenobarbital; PCV: procarbazine, CCNU, vincristine; PHT, phenytoin; VPA, valproic acid; Cl, clearance; T 1/2, plasma drug elimination half-life; AUC, area under time-concentration curve; MTD, maximum tolerated dose; nEI, MTD without EIAEDs; EI, MTD with EIAEDs and corresponding Cl, T 1/2, or AUC.