PMID- 29961161
OWN - NLM
STAT- MEDLINE
DCOM- 20190926
LR  - 20191210
IS  - 1573-8744 (Electronic)
IS  - 1567-567X (Linking)
VI  - 45
IP  - 5
DP  - 2018 Oct
TI  - Joint longitudinal model development: application to exposure-response modeling 
      of ACR and DAS scores in rheumatoid arthritis patients treated with sirukumab.
PG  - 679-691
LID - 10.1007/s10928-018-9598-5 [doi]
AB  - Exposure-response modeling is important to optimize dose and dosing regimen in 
      clinical drug development. The joint modeling of multiple endpoints is made 
      possible in part by recent progress in latent variable indirect response (IDR) 
      modeling for ordered categorical endpoints. This manuscript presents the results 
      of joint modeling of continuous and ordered categorical endpoints in the latent 
      variable IDR modeling framework through the sharing of model parameters, with an 
      application to the exposure-response modeling of sirukumab. Sirukumab is a human 
      anti- interleukin-6 (IL-6) monoclonal antibody that binds soluble human IL-6 thus 
      blocking IL-6 signaling, which plays a major role in the pathophysiology of 
      rheumatoid arthritis (RA). A phase 2 clinical trial was conducted in patients 
      with active RA despite methotrexate therapy, who received subcutaneous (SC) 
      administration of either placebo or sirukumab of 25, 50 or 100 mg every 4 weeks 
      (q4w) or 100 mg every 2 weeks (q2w). Major efficacy endpoints were the 20, 50, 
      and 70% improvement in the American College of Rheumatology (ACR20, ACR50, and 
      ACR70) disease severity criteria, and the 28-joint disease activity score using 
      C-reactive protein (DAS28). The ACR endpoints were treated as ordered categorical 
      and DAS28 as continuous. The results showed that, compared with the common 
      approach of separately modeling the endpoints, the joint model could describe the 
      observed data better with fewer parameters through the sharing of random effects, 
      and thus more precisely characterize the dose-response relationship. The 
      implications on future dose and dosing regimen optimization are discussed in 
      contrast with those from landmark analysis.
FAU - Hu, Chuanpu
AU  - Hu C
AUID- ORCID: 0000-0001-7812-2778
AD  - Global Clinical Pharmacology, Janssen Research & Development, LLC, PO Box 776, 
      1400 McKean Road, Spring House, PA, 19477, USA. CHu25@its.jnj.com.
FAU - Xu, Yan
AU  - Xu Y
AD  - Global Clinical Pharmacology, Janssen Research & Development, LLC, PO Box 776, 
      1400 McKean Road, Spring House, PA, 19477, USA.
FAU - Zhuang, Yanli
AU  - Zhuang Y
AD  - Global Clinical Pharmacology, Janssen Research & Development, LLC, PO Box 776, 
      1400 McKean Road, Spring House, PA, 19477, USA.
FAU - Hsu, Benjamin
AU  - Hsu B
AD  - Clinical Development, Janssen Research & Development, LLC, PO Box 776, 1400 
      McKean Road, Spring House, PA, 19477, USA.
FAU - Sharma, Amarnath
AU  - Sharma A
AD  - Global Clinical Pharmacology, Janssen Research & Development, LLC, PO Box 776, 
      1400 McKean Road, Spring House, PA, 19477, USA.
FAU - Xu, Zhenhua
AU  - Xu Z
AD  - Global Clinical Pharmacology, Janssen Research & Development, LLC, PO Box 776, 
      1400 McKean Road, Spring House, PA, 19477, USA.
FAU - Zhang, Liping
AU  - Zhang L
AD  - Global Clinical Pharmacology, Janssen Research & Development, LLC, PO Box 776, 
      1400 McKean Road, Spring House, PA, 19477, USA.
FAU - Zhou, Honghui
AU  - Zhou H
AD  - Global Clinical Pharmacology, Janssen Research & Development, LLC, PO Box 776, 
      1400 McKean Road, Spring House, PA, 19477, USA.
LA  - eng
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20180630
PL  - United States
TA  - J Pharmacokinet Pharmacodyn
JT  - Journal of pharmacokinetics and pharmacodynamics
JID - 101096520
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antirheumatic Agents)
RN  - 0 (Interleukin-6)
RN  - 640443FU93 (sirukumab)
RN  - 9007-41-4 (C-Reactive Protein)
RN  - YL5FZ2Y5U1 (Methotrexate)
SB  - IM
MH  - Antibodies, Monoclonal/*therapeutic use
MH  - Antibodies, Monoclonal, Humanized
MH  - Antirheumatic Agents/*therapeutic use
MH  - Arthritis, Rheumatoid/*drug therapy/metabolism
MH  - C-Reactive Protein/metabolism
MH  - Double-Blind Method
MH  - Endpoint Determination/methods
MH  - Humans
MH  - Injections, Subcutaneous/methods
MH  - Interleukin-6/metabolism
MH  - Longitudinal Studies
MH  - Methotrexate/therapeutic use
OTO - NOTNLM
OT  - Bounded outcome score
OT  - Discrete variable
OT  - Joint modeling
OT  - NONMEM
OT  - Population pharmacokinetic/pharmacodynamic modeling
EDAT- 2018/07/02 06:00
MHDA- 2019/09/27 06:00
CRDT- 2018/07/02 06:00
PHST- 2018/02/07 00:00 [received]
PHST- 2018/06/25 00:00 [accepted]
PHST- 2018/07/02 06:00 [pubmed]
PHST- 2019/09/27 06:00 [medline]
PHST- 2018/07/02 06:00 [entrez]
AID - 10.1007/s10928-018-9598-5 [pii]
AID - 10.1007/s10928-018-9598-5 [doi]
PST - ppublish
SO  - J Pharmacokinet Pharmacodyn. 2018 Oct;45(5):679-691. doi: 
      10.1007/s10928-018-9598-5. Epub 2018 Jun 30.