Pharmacokinetics of sepantronium bromide (YM155), a small-molecule suppressor of survivin, in Japanese patients with advanced solid tumors: dose proportionality and influence of renal impairment.
OBJECTIVE
The purpose of this analysis was to investigate the pharmacokinetics (PK) of sepantronium (YM155), a small-molecule suppressor of the expression of the antiapoptosis protein survivin, in Japanese patients with advanced solid tumors and to evaluate the effect of renal impairment on the PK profile of sepantronium.


METHODS
Sepantronium was administered as a continuous intravenous infusion of 1.8-10.6 mg/m(2)/day for 168 h (7 days) to 33 patients. PK parameters were estimated via non-compartmental method. Renal function was categorized for the analysis based on the chronic kidney disease guidance using eGFR values at pre-dose.


RESULTS
The PK of sepantronium was dose proportional in the dose range of 1.8-10.6 mg/m(2)/day. Age and sex did not significantly affect the PK of sepantronium. Results suggested that total clearance and renal clearance in patients with moderate renal impairment were 0.7-fold lower than those in patients with normal renal function, resulting in 1.3-fold higher steady-state concentration and area under the curve values. The PK parameters of sepantronium in patients with mild renal impairment were comparable to those in the patients with normal renal function.


CONCLUSIONS
While age and sex did not significantly affect the PK of sepantronium, moderate renal impairment increased exposure of sepantronium by about 30 %. The results suggest that no dose adjustment is required for patients with mild renal impairment.
Clinical Pharmacology, Development, Astellas Pharma Inc., Hasune, Itabashi-ku, Tokyo, Japan. yumiko.aoyama@astellas.com
Yumiko
Y
Aoyama
Tetsuya
T
Nishimura
Taiji
T
Sawamoto
Taroh
T
Satoh
Masataka
M
Katashima
Kazuhiko
K
Nakagawa
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D044466:Asian People; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors; D007564:Japan; D008297:Male; D008875:Middle Aged; D009285:Naphthoquinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051437:Renal Insufficiency / Q000150:complications* / Q000503:physiopathology; D012189:Retrospective Studies; D012737:Sex Factors; D000077022:Survivin
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D000077022:Survivin; C523798:sepantronium