PMID- 25782535
OWN - NLM
STAT- MEDLINE
DCOM- 20160603
LR  - 20181113
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 80
IP  - 3
DP  - 2015 Sep
TI  - Impact of dosing regimen of custirsen, an antisense oligonucleotide, on safety, 
      tolerability and cardiac repolarization in healthy subjects.
PG  - 436-45
LID - 10.1111/bcp.12633 [doi]
AB  - AIMS: Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide 
      (ASO) that reduces clusterin production, is under investigation with chemotherapy 
      in patients with solid tumours. Custirsen is associated with constitutional 
      symptoms (CS) that may interfere with clinical pharmacology investigations, such 
      as QT interval studies. Experience with other ASOs suggests NSAID premedication 
      may ameliorate CS, but we observed suboptimal outcomes in healthy subjects given 
      custirsen and NSAIDs. We sought to establish a custirsen regimen for future 
      clinical pharmacology studies in healthy subjects. METHODS: Subjects received 
      custirsen (640 mg intravenously over 120 min) with dexamethasone premedication or 
      increasing doses (320, 480, 640 mg over 6 days) of custirsen with dexamethasone 
      premedication, then one full custirsen dose without premedication on day 8. 
      Incidence/severity of adverse events (AEs) and extensive electrocardiogram 
      readings were evaluated. Pharmacokinetic parameters were estimated. RESULTS: AEs 
      included CS, elevated transaminases and prolonged activated partial 
      thromboplastin time (aPTT) that were predominantly grade 1/2. Administration of 
      increasing custirsen doses and dexamethasone premedication reduced the incidence 
      of CS associated with full dose custirsen. Transaminase elevation showed a 
      dose-dependent effect (0% at days 2, 4, 27% at day 6) with the highest custirsen 
      doses. Increasing doses of custirsen may have mitigated the severity but not 
      incidence of aPTT prolongation. Neither regimen was associated with cardiac 
      repolarization changes in QT values or concentration-effect analyses. The 
      custirsen pharmacokinetic profile was consistent with previous experience. 
      CONCLUSION: Escalation of custirsen dose combined with dexamethasone 
      premedication reduced CS associated with full dose custirsen and should be 
      considered in future clinical pharmacology studies of custirsen.
CI  - (c) 2015 The British Pharmacological Society.
FAU - Rabinovich-Guilatt, Laura
AU  - Rabinovich-Guilatt L
AD  - Teva Pharmaceuticals Industries Ltd., Netanya, Israel.
FAU - Elgart, Anna
AU  - Elgart A
AD  - Teva Pharmaceuticals Industries Ltd., Netanya, Israel.
FAU - Erisson, Lavi
AU  - Erisson L
AD  - Codega Holdings LLC, Irvington, NY, USA.
FAU - Willsie, Sandra K
AU  - Willsie SK
AD  - PRA Health Sciences, Lenexa, Kansas, USA.
FAU - Tessler, Shoshi
AU  - Tessler S
AD  - Teva Pharmaceuticals Industries Ltd., Netanya, Israel.
FAU - Barnett-Griness, Ofra
AU  - Barnett-Griness O
AD  - Teva Pharmaceuticals Industries Ltd., Netanya, Israel.
FAU - Pande, Amitkumar
AU  - Pande A
AD  - Teva Pharmaceutical Industries Ltd., Frazer, PA, USA.
FAU - Spiegelstein, Ofer
AU  - Spiegelstein O
AD  - Teva Pharmaceuticals Industries Ltd., Netanya, Israel.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150622
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (OGX-011)
RN  - 0 (Oligonucleotides, Antisense)
RN  - 0 (Thionucleotides)
RN  - 7S5I7G3JQL (Dexamethasone)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Anti-Inflammatory Agents/administration & dosage/*therapeutic use
MH  - Antineoplastic Agents/administration & dosage/*adverse effects/pharmacokinetics
MH  - Cross-Over Studies
MH  - Dexamethasone/administration & dosage/*therapeutic use
MH  - Dose-Response Relationship, Drug
MH  - Electrocardiography
MH  - Electrocardiography, Ambulatory/drug effects
MH  - Healthy Volunteers
MH  - Humans
MH  - Infusions, Intravenous
MH  - Long QT Syndrome/chemically induced/diagnosis
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Oligonucleotides, Antisense/administration & dosage/*adverse 
      effects/pharmacokinetics
MH  - Premedication
MH  - Thionucleotides/administration & dosage/*adverse effects/pharmacokinetics
MH  - Young Adult
PMC - PMC4574829
OTO - NOTNLM
OT  - antisense oligonucleotides
OT  - cardiac safety
OT  - custirsen
OT  - healthy subjects
OT  - pharmacokinetics
OT  - thorough QT
EDAT- 2015/03/19 06:00
MHDA- 2016/06/04 06:00
PMCR- 2016/09/01
CRDT- 2015/03/19 06:00
PHST- 2014/10/31 00:00 [received]
PHST- 2015/02/13 00:00 [revised]
PHST- 2015/03/12 00:00 [accepted]
PHST- 2015/03/19 06:00 [entrez]
PHST- 2015/03/19 06:00 [pubmed]
PHST- 2016/06/04 06:00 [medline]
PHST- 2016/09/01 00:00 [pmc-release]
AID - 10.1111/bcp.12633 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2015 Sep;80(3):436-45. doi: 10.1111/bcp.12633. Epub 2015 Jun 
      22.