Single-Dose Pharmacokinetics, Safety, and Tolerability of Avadomide (CC-122) in Subjects With Mild, Moderate, or Severe Renal Impairment

© 2019, The American College of Clinical Pharmacology..

CC-122 (Avadomide) is a nonphthalimide analogue of thalidomide that has multiple pharmacological activities including immune modulation of several immune cell subsets, antigrowth activity, antiproliferative activity, and antiangiogenic activity. CC-122 as monotherapy and in combination with other agents is being evaluated for multiple indications including hematologic malignancies and advanced solid tumors. Given that renal clearance is one of the major routes of elimination for CC-122 and its clearance/exposure could be affected by renal impairment, a total of 50 subjects with various degrees of renal function were enrolled in an open-label, single-dose study to evaluate the impact of renal impairment on CC-122 pharmacokinetic disposition. The study showed that following administration of a single oral dose of 3 mg CC-122, renal impairment reduced both the apparent total plasma clearance and renal clearance of CC-122, but it had less impact on CC-122 absorption, as demonstrated by similar Tmax and Cmax among groups with various degrees of renal function. Compared with exposure in subjects with normal renal function, total plasma exposure to CC-122 increased by ∼20%, ∼50%, and ∼120% in subjects with mild, moderate, and severe renal insufficiency, respectively. Results from this study combined with modeling/simulation suggest that dose adjustments are necessary in patients with moderate or severe but not with mild renal impairment. Finally, a single dose of 3 mg CC-122 was safe and well tolerated by healthy subjects and subjects with mild, moderate, and severe renal impairment.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:9

Enthalten in:

Clinical pharmacology in drug development - 9(2020), 7 vom: 31. Okt., Seite 785-796

Sprache:

Englisch

Beteiligte Personen:

Li, Yan [VerfasserIn]
MacGorman, Kimberly [VerfasserIn]
Liu, Liangang [VerfasserIn]
Chen, Jian [VerfasserIn]
Hoffmann, Matthew [VerfasserIn]
Palmisano, Maria [VerfasserIn]
Zhou, Simon [VerfasserIn]

Links:

Volltext

Themen:

3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione
Adaptor Proteins, Signal Transducing
Avadomide
CC-122
CRBN protein, human
Clinical Trial, Phase I
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 CYP3A Inhibitors
EC 2.3.2.27
Journal Article
Multicenter Study
Pharmacokinetics
Piperidones
Quinazolinones
Renal impairment
Research Support, Non-U.S. Gov't
Safety
Tolerability
Ubiquitin-Protein Ligases

Anmerkungen:

Date Completed 09.08.2021

Date Revised 09.08.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1002/cpdd.760

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM304911690