Marginal increase of sunitinib exposure by grapefruit juice.
OBJECTIVE
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 steady-state 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 (AUC(0-24 h)) from 122.1 to 182.0 ng h/mL (P = 0.034).


CONCLUSIONS
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.
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. p.h.van_erp@lumc.nl
Nielka P
NP
van Erp
Sharyn D
SD
Baker
Anthe S
AS
Zandvliet
Bart A
BA
Ploeger
Margaret
M
den Hollander
Zhaoyuan
Z
Chen
Jan
J
den Hartigh
Jacqueline M C
JM
König-Quartel
Henk-Jan
HJ
Guchelaar
Hans
H
Gelderblom
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001628:Beverages / Q000009:adverse effects; D001682:Biological Availability; D032083:Citrus paradisi / Q000009:adverse effects*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004348:Drug Labeling; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008874:Midazolam / Q000378:metabolism; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077210:Sunitinib
D000970:Antineoplastic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D007211:Indoles; D011758:Pyrroles; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; D000077210:Sunitinib