Sunitinib - Drug-Drug Interactions

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

1. Food and Drug Administration. Sunitinib (Sutent) Prescribing information. 2015.
2. European Medicines Agency. Sunitinib (SUTENT). Summary of Product Characteristics. 2015.
3. 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.
4. 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.
5. 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.
6. Bilbao-Meseguer I, Jose BS, Lopez-Gimenez LR et al. Drug interactions with sunitinib. J Oncol Pharm Pract 2015; 21: 52-66.