PMID- 19014836
OWN - NLM
STAT- MEDLINE
DCOM- 20090209
LR  - 20131121
IS  - 0149-2918 (Print)
IS  - 0149-2918 (Linking)
VI  - 30
IP  - 10
DP  - 2008 Oct
TI  - Pharmacokinetic and pharmacodynamic properties of TRU-015, a CD20-directed small 
      modular immunopharmaceutical protein therapeutic, in patients with rheumatoid 
      arthritis: a Phase I, open-label, dose-escalation clinical study.
PG  - 1806-16
LID - 10.1016/j.clinthera.2008.10.017 [doi]
AB  - BACKGROUND: TRU-015 is a small modular immunopharmaceutical protein drug that 
      binds to CD20 and effectively depleted B cells in nonhuman primates. OBJECTIVE: 
      The aim of this clinical study was to determine the pharmacokinetic (PK) and 
      pharmacodynamic (PD) properties, immunogenicity, and tolerability of TRU-015 in 
      patients with rheumatoid arthritis (RA). METHODS: This Phase I, open-label, 
      dose-escalation clinical study was conducted at 4 medical centers in the United 
      States. Patients with RA who were receiving stable-dose methotrexate were 
      enrolled in 1 of 8 dose groups and received TRU-015 as a single IV dose of 0.015, 
      0.05, 0.15, 0.5, 1.5, 5, or 15, or 2 IV doses of 15 mg/kg, administered 7 days 
      apart (30 mg/kg). Patients were enrolled in the next higher dose cohort based on 
      the tolerability observed in the prior cohort. Prior to TRU-015 infusion, 
      patients were premedicated with an antihistamine and acetaminophen and may have 
      received a corticosteroid at the investigator's discretion. Serum samples were 
      collected for analysis of PK properties (serum t((1/2))) and neutralizing 
      antibodies to TRU-015; enzyme-linked immunosorbent assays and a cell-based 
      neutralizing assay were used to evaluate samples from patients. PD response was 
      measured using B-cell (CD19(+)-cell) count using flow cytometry at prespecified 
      time points. Tolerability was assessed during drug infusion and at prespecified 
      time points after infusion using physical examination and laboratory analysis. 
      Patients were followed for >or=4 weeks and until B-cell recovery. RESULTS: 
      Thirty-seven patients were enrolled. Most were female (81%) and white (95%); the 
      mean age was 53 years. Serum t((1/2)) ranged from 12 to 19 days. B-cell depletion 
      generally increased in degree and duration with increasing doses. No neutralizing 
      antibodies to TRU-015 were detected. Mild adverse events (AEs) included back 
      pain, headache, peripheral edema, and upper respiratory infection (5 patients 
      each). Mild urticaria occurred in 1 patient. Grade 3 AEs included hypertension, 
      arthralgia, and urticaria and bronchospasm (1 patient each). No dose-limiting 
      toxicity was found. CONCLUSIONS: In this small population of patients with RA, 
      the C(max) and the AUC appeared to increase in a dose-proportional manner. The 
      mean t((1/2)) ranged from 12 to 19 days. TRU-015 was associated with 
      dose-dependent B-cell depletion and an acceptable tolerability profile.
FAU - Burge, Daniel J
AU  - Burge DJ
AD  - Trubion Pharmaceuticals Inc., Seattle, Washington, USA.
FAU - Bookbinder, Stephen A
AU  - Bookbinder SA
FAU - Kivitz, Alan J
AU  - Kivitz AJ
FAU - Fleischmann, Roy M
AU  - Fleischmann RM
FAU - Shu, Cathye
AU  - Shu C
FAU - Bannink, Jeannette
AU  - Bannink J
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PL  - United States
TA  - Clin Ther
JT  - Clinical therapeutics
JID - 7706726
RN  - 0 (Antigens, CD19)
RN  - 0 (Antirheumatic Agents)
RN  - 0 (Peptides)
RN  - YL5FZ2Y5U1 (Methotrexate)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antigens, CD19/immunology
MH  - Antirheumatic Agents/administration & dosage/*pharmacokinetics/*therapeutic use
MH  - Area Under Curve
MH  - Arthritis, Rheumatoid/*drug therapy/immunology
MH  - B-Lymphocytes/immunology
MH  - Dose-Response Relationship, Drug
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Female
MH  - Half-Life
MH  - Humans
MH  - Injections, Intravenous
MH  - Male
MH  - Metabolic Clearance Rate
MH  - Methotrexate/therapeutic use
MH  - Middle Aged
MH  - Peptides/administration & dosage/*pharmacology/*therapeutic use
MH  - Young Adult
EDAT- 2008/11/19 09:00
MHDA- 2009/02/10 09:00
CRDT- 2008/11/19 09:00
PHST- 2008/08/27 00:00 [accepted]
PHST- 2008/11/19 09:00 [pubmed]
PHST- 2009/02/10 09:00 [medline]
PHST- 2008/11/19 09:00 [entrez]
AID - S0149-2918(08)00338-X [pii]
AID - 10.1016/j.clinthera.2008.10.017 [doi]
PST - ppublish
SO  - Clin Ther. 2008 Oct;30(10):1806-16. doi: 10.1016/j.clinthera.2008.10.017.