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Pharmacokinetics of ixazomib, an oral proteasome inhibitor, in solid tumour patients with moderate or severe hepatic impairment.
- Source :
-
British journal of clinical pharmacology [Br J Clin Pharmacol] 2016 Sep; Vol. 82 (3), pp. 728-38. Date of Electronic Publication: 2016 May 29. - Publication Year :
- 2016
-
Abstract
- Aim: 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.<br />Methods: 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.<br />Results: 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.<br />Conclusions: 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.<br /> (© 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)
- Subjects :
- Administration, Oral
Adult
Aged
Aged, 80 and over
Boron Compounds administration & dosage
Boron Compounds blood
Female
Glycine administration & dosage
Glycine blood
Glycine pharmacokinetics
Humans
Liver Diseases complications
Liver Diseases drug therapy
Male
Middle Aged
Neoplasms complications
Neoplasms drug therapy
Proteasome Inhibitors administration & dosage
Proteasome Inhibitors blood
Proteasome Inhibitors pharmacokinetics
Young Adult
Boron Compounds pharmacokinetics
Glycine analogs & derivatives
Liver Diseases blood
Neoplasms blood
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2125
- Volume :
- 82
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- British journal of clinical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 27121262
- Full Text :
- https://doi.org/10.1111/bcp.12991