Relationship Between Sunitinib Pharmacokinetics and Administration Time: Preclinical and Clinical Evidence

Abstract

Background and ObjectiveCircadian rhythms may influence the pharmacokinetics of drugs. This study aimed to elucidate whether the pharmacokinetics of the orally administered drug sunitinib are subject to circadian variation.MethodsWe performed studies in male FVB-mice aged 8–12 weeks, treated with single-dose sunitinib at six dosing times. Plasma and tissue samples were obtained for pharmacokinetic analysis and to monitor messenger RNA (mRNA) expression of metabolizing enzymes and drug transporters. A prospective randomized crossover study was performed in which patients took sunitinib once daily at 8 a.m., 1 p.m., and 6 p.m at three subsequent courses. Patients were blindly randomized into two groups, which determined the sequence of the sunitinib dosing time. The primary endpoint in both studies was the difference in plasma area under the concentration–time curve (AUC) of sunitinib and its active metabolite SU12662 between dosing times.ResultsSunitinib and SU12662 plasma AUC in mice followed an ~12-h rhythm as a function of administration time (p ≤ 0.04). The combined AUC from time zero to 10 h (AUC10) was 14–27 % higher when sunitinib was administered at 4 a.m. and 4 p.m. than at 8 a.m. and 8 p.m. Twenty-four-hour rhythms were seen in the mRNA levels of drug transporters and metabolizing enzymes. In 12 patients, sunitinib trough concentrations (Ctrough) were higher when the drug was taken at 1 p.m. or 6 p.m. than when taken at 8 a.m. (Ctrough-1 p.m. 66.0 ng/mL; Ctrough-6 p.m. 58.9 ng/mL; Ctrough-8 a.m. 50.7 ng/mL; p = 0.006). The AUC was not significantly different between dosing times.ConclusionsOur results indicate that sunitinib pharmacokinetics follow an ~12-h rhythm in mice. In humans, morning dosing resulted in lower Ctrough values, probably resulting from differences in elimination. This can have implications for therapeutic drug monitoring.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-015-0239-5) contains supplementary material, which is available to authorized users.

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“…Enzymes and transporters involved in the pharmacokinetics of drugs, such as CYP3A4 and ABCB1, have timedependent variations in expression which may have profound effect on the exposure to several drugs. Kloth & al (Kloth et al, 2015) found that sunitinib trough plasma concentrations were significantly lower when patients were administered sunitinib in the morning, than at noon or in the evening. However, AUC was not significantly different when sunitinib was administered at different time of the day.…”