Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment.
The aim of the present study was to characterize the pharmacokinetics of the oral proteasome inhibitor, ixazomib, in patients with solid tumours and moderate or severe hepatic impairment, to provide posology recommendations.



Eligible adults with advanced malignancies for which no further effective therapy was available received a single dose of ixazomib on day 1 of the pharmacokinetic cycle; patients with normal hepatic function, moderate hepatic impairment or severe hepatic impairment received 4 mg, 2.3 mg or 1.5 mg, respectively. Blood samples for single-dose pharmacokinetic characterization were collected over 336 h postdose. After sampling, patients could continue to receive ixazomib on days 1, 8 and 15 in 28-day cycles.



Of 48 enrolled patients (13, 15 and 20 in the normal, moderate and severe groups, respectively), 43 were pharmacokinetics-evaluable. Ixazomib was rapidly absorbed (median time to reach peak concentration was 0.95-1.5 h) and highly bound to plasma proteins, with a similar mean fraction bound (~99%) across the three groups. In patients with moderate/severe hepatic impairment (combined group), the geometric least squares mean ratios (90% confidence interval) for unbound and total dose-normalized area under the plasma concentration vs. time curve from time zero to the time of the last quantifiable concentration in reference to the normal hepatic function group were 1.27 (0.75, 2.16) and 1.20 (0.79, 1.82), respectively. Seven (15%) of the 48 patients experienced a grade 3 drug-related adverse event; there were no drug-related grade 4 adverse events.



In patients with moderate/severe hepatic impairment, unbound and total systemic exposures of ixazomib were 27% and 20% higher, respectively, vs. normal hepatic function. A reduced ixazomib starting dose of 3 mg is recommended for patients with moderate or severe hepatic impairment.
Millennium Pharmaceuticals, Inc., Cambridge, MA, USA.
Neeraj
N
Gupta
Millennium Pharmaceuticals, Inc., Cambridge, MA, USA.
Michael J
MJ
Hanley
Millennium Pharmaceuticals, Inc., Cambridge, MA, USA.
Karthik
K
Venkatakrishnan
University of Kansas Clinical Research Center, Fairway, KS, USA.
Raymond
R
Perez
University Hospitals of Cleveland, Cleveland, OH, USA.
Robin E
RE
Norris
Mary Crowley Cancer Research Centers, Dallas, TX, USA.
John
J
Nemunaitis
Millennium Pharmaceuticals, Inc., Cambridge, MA, USA.
Huyuan
H
Yang
Millennium Pharmaceuticals, Inc., Cambridge, MA, USA.
Mark G
MG
Qian
Sarah Cannon Research Institute at HealthONE, Denver, CO, USA.
Gerald
G
Falchook
Millennium Pharmaceuticals, Inc., Cambridge, MA, USA.
Richard
R
Labotka
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Siqing
S
Fu
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001896:Boron Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D008107:Liver Diseases / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D061988:Proteasome Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
D001896:Boron Compounds; D061988:Proteasome Inhibitors; C548400:ixazomib; D005998:Glycine
hepatic impairment; ixazomib; phase 1 clinical trial; proteasome inhibitor; solid tumours