The main drug-drug interactions associated with sunitinib include
CYP3A4 Inhibitors/ Inducers
CYP3A4 Inhibitors
Concomitant administration of sunitinib and ketoconazole increased the combined Cmax and AUC0-inf for sunitinib and its primary metabolite by 49% and 51%, respectively.1,2 (See also: QTc interval-prolonging drugs)
HIV-positive cancer patients receiving ritonavir as part of highly active antiretroviral therapy (HAART) experienced dose-limiting toxicity on sunitinib 37.5 mg/day, whereas patients receiving non-ritonavir HAART tolerated standard sunitinib dosing.3 Ritonavir reduced exposure to the active metabolite N-desethyl sunitinib.1,2
CYP3A4 Inducers
Concomitant administration of sunitinib and rifampicin reduced the combined Cmax and AUC0-inf for sunitinib and its primary metabolite by 23% and 46%, respectively.2 Efavirenz, administered as part of HAART to cancer patients with HIV, resulted in increased exposure to the active metabolite N-desethyl sunitinib.3,4 Other CYP3A4 inducers, such as dexamethasone, phenytoin, carbamazepine and phenobarbital are likely to have similar effects, although evidence is limited.4
QT Prolongators
QTc Interval-Prolonging Drugs
Sunitinib prolongs the QTc interval, possibly by inhibiting cardiac repolarisation.4 Prolongation of the QTc interval occurs in a dose-dependent manner;1,2 concomitant administration of strong CYP3A4 inhibitors that may increase sunitinib plasma concentrations should therefore be avoided.2 Concomitant use of sunitinib with other QTc interval-prolonging drugs may significantly prolong the QTc interval.5
Other Drug-drug Interactions
Sunitinib and Antineoplastic Agents
Co-administration of sunitinib and ifosfamide significantly decreased exposure to sunitinib in patients with solid tumours (See below: CYP3A4 inducers).5
P-glycoprotein Substrates
Sunitinib is a P-glycoprotein inhibitor. Extensive monitoring is recommended if P-glycoprotein substrates with a narrow therapeutic window are co-administered.5
ABCG2 Substrates
Sunitinib is known to interact with substrates of ABCG2 (breast cancer resistance protein; BCRP).6
References
- Food and Drug Administration. Sunitinib (Sutent) Prescribing information. 2015.
- European Medicines Agency. Sunitinib (SUTENT). Summary of Product Characteristics. 2015.
- Rudek MA, Moore PC, Mitsuyasu RT et al. A phase 1/pharmacokinetic study of sunitinib in combination with highly active antiretroviral therapy in human immunodeficiency virus-positive patients with cancer: AIDS Malignancy Consortium trial AMC 061. Cancer 2014; 120: 1194-1202.
- Pajares B, Torres E, Trigo JM et al. Tyrosine kinase inhibitors and drug interactions: a review with practical recommendations. Clin Transl Oncol 2012; 14: 94-101.
- van Leeuwen RW, van Gelder T, Mathijssen RH, Jansman FG. Drug-drug interactions with tyrosine-kinase inhibitors: a clinical perspective. Lancet Oncol 2014; 15: e315-326.
- Bilbao-Meseguer I, Jose BS, Lopez-Gimenez LR et al. Drug interactions with sunitinib. J Oncol Pharm Pract 2015; 21: 52-66.