Marginal increase of sunitinib exposure by grapefruit juice Nielka P. van ErpSharyn D. BakerAnthe S. ZandvlietBart A. Ploeger • Margaret den HollanderZhaoyuan ChenJan den Hartigh • Jacqueline M. C. Konig-QuartelHenk-Jan GuchelaarHans Gelderblom

Purpose The drug label of sunitinib includes a warning for concomitant use of grapefruit juice (GJ) but clinical evidence for this drug interaction is lacking. The aim of this study is to determine the effect of GJ, a potent intestinal cytochrome P450 (CYP) 3A4 inhibitor, on steadystate sunitinib pharmacokinetics (PK). Methods Sunitinib PK was evaluated in eight cancer patients receiving sunitinib monotherapy in a ‘‘4 weeks on—2 weeks off’’ dose regimen. Serial blood samples for PK analysis of sunitinib were collected on two separate days. On both PK days, patients received a single oral dose of 7.5-mg midazolam as a phenotypic probe for assessment of intestinal CYP3A4 activity. The first PK day was at steady-state sunitinib PK (between days 14–20), the second PK day was on day 28. On days 25, 26 and 27, 200-mL GJ was consumed 3 times a day. The effect of GJ on sunitinib exposure was assessed by comparing sunitinib PK with and without GJ. Results Concomitant use of GJ and sunitinib resulted in an 11% increase of the relative bioavailability of sunitinib (P \ 0.05). The effect of GJ on CYP3A4 activity was confirmed by an increase of*50% of mean midazolam exposure (AUC0–24 h) from 122.1 to 182.0 ng h/mL (P = 0.034). Conclusion GJ consumption results in a marginal increase in sunitinib exposure which is not considered clinically relevant. There is no clinical evidence underscoring the warning in the sunitinib drug label regarding concomitant use of GJ.