This is the first case in which the accumulation of
N-desethyl sunitinib was reported to cause serious adverse events, even when the total sunitinib concentration was under the reported trough value of 50 ng/mL. Our data suggest that in this patient,
N-desethyl sunitinib accumulated because of delayed excretion, resulting in the described adverse effects. The patient’s
N-desethyl sunitinib plasma levels (21.4 ng/mL) while taking 25 mg sunitinib were higher than the steady-state levels (18.8 ng/mL) of patients administered 50 mg sunitinib daily [
7]. The elimination half-lives of sunitinib and
N-desethyl sunitinib have been reported as 70 hours and 111 hours, respectively, in patients with end-stage renal disease requiring hemodialysis [
10]; the corresponding half-lives of this patient were 51 hours and 211 hours. Moreover, the reported trough level ratio (
N-desethyl sunitinib/sunitinib) is 0.43 [
7], but was above 1.0 in this patient. In addition, it has been reported that thrombocytopenia is more frequently associated with
N-desethyl sunitinib rather than sunitinib [
13]. On the basis of these data, we conclude that the cause of the grade 3 hematologic toxicities was the accumulation of
N-desethyl sunitinib. Despite the fact that the use of concomitant medications, health supplements, and grapefruit have been found to affect the main metabolic enzyme of sunitinib, CYP 3A4, our patient did not consume them; therefore, it was considered unlikely that the accumulation of
N-desethyl sunitinib was the result of any of these factors. Although the reason for the delayed excretion of
N-desethyl sunitinib in this patient was unknown, we suggest it was caused by genetic polymorphisms affecting the pharmacokinetics of sunitinib rather than by the hemodialysis. It has been reported that the gene polymorphism in
ABCG2 421C >
A can induce severe toxicity by delaying the excretion of sunitinib [
14], but the patient in this case had a wild-type
ABCG2. However, there may be other gene polymorphisms, such as those described for ATP-binding cassette subfamily B member 1, which function as an efflux pump of sunitinib and can thus affect the clinical outcome [
15]. Furthermore,
N-desethyl sunitinib is further metabolized and excreted in the urine [
16,
17]. This excretion process can be inhibited by the interaction with transporters such as the organic ion transporter. In addition, previous research has shown that the incidence of severe hematological toxicities is demonstrably higher in Japanese patients than in other populations, but that the pharmacokinetic data from Japanese patients is similar to that of Caucasians [
18]. Thus, ethnic differences in sunitinib-induced hematologic toxicities could be attributed to factors other than the pharmacokinetic genetic background.
Although the evidence for use of TDM of sunitinib in a clinical setting is limited, this case report demonstrates that TDM can be useful for predicting and avoiding severe adverse events. Further studies would be needed to select patients suitable for TDM with gene polymorphisms, severe adverse events, and no antitumor effects.