PMID- 32333684
OWN - NLM
STAT- MEDLINE
DCOM- 20210709
LR  - 20210709
IS  - 1552-4604 (Electronic)
IS  - 0091-2700 (Linking)
VI  - 60
IP  - 8
DP  - 2020 Aug
TI  - Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Modeling of 
      Weight-Based Intravenous Reslizumab Dosing.
PG  - 1039-1050
LID - 10.1002/jcph.1609 [doi]
AB  - Reslizumab 3.0 mg/kg has demonstrated efficacy in clinical studies of patients 
      with eosinophilic asthma and a history of exacerbations. A population 
      pharmacokinetic (PK) model was developed to determine whether 3.0 mg/kg 
      weight-based dosing is appropriate to obtain consistent reslizumab exposures in 
      all patients. PK data in healthy volunteers and patients >/=12 years with moderate 
      to severe asthma, eosinophilic asthma, or nasal polyposis were analyzed from 4 
      phase 1, 2 phase 2, and 2 phase 3 studies of intravenous (IV) reslizumab (N = 
      804). Covariates evaluated included age, race, sex, baseline weight, renal and 
      liver function, concomitant medications, and antidrug antibody status. 
      Exposure-response models were developed to characterize key efficacy (blood 
      eosinophil levels, forced expiratory volume in 1 second [FEV(1) ], Asthma Control 
      Questionnaire [ACQ-7] scores), and safety end points (muscle disorder adverse 
      events [AEs]). Vial-based dosing was evaluated as an alternative to weight-based 
      dosing. IV reslizumab PK was accurately described by a 2-compartment PK model 
      with 0-order input and first-order elimination. Body weight was the only 
      covariate that significantly influenced PK parameters. However, with weight-based 
      dosing, comparable steady-state exposures were observed across high and low body 
      weights. Greater eosinophil lowering and longer response duration were observed 
      with increasing dose; exposure-related effects on FEV(1) and ACQ-7 were also 
      seen, demonstrating the clinical importance of a dosing regimen to optimize 
      reslizumab exposure. The probability of a muscle disorder AE appeared to increase 
      with increasing exposure. Steady-state exposure measures were similar for both 
      dosing regimens, showing vial-based dosing as an alternative method of achieving 
      the benefits of weight-based dosing.
CI  - (c) 2020, The American College of Clinical Pharmacology.
FAU - Passarell, Julie
AU  - Passarell J
AD  - Cognigen Corporation, a Simulations Plus company, Buffalo, New York, USA.
FAU - Jaworowicz, David
AU  - Jaworowicz D
AD  - Cognigen Corporation, a Simulations Plus company, Buffalo, New York, USA.
FAU - Ludwig, Elizabeth
AU  - Ludwig E
AD  - Cognigen Corporation, a Simulations Plus company, Buffalo, New York, USA.
FAU - Rabinovich-Guilatt, Laura
AU  - Rabinovich-Guilatt L
AD  - Teva Branded Pharmaceutical Products R&D Inc, West Chester, Pennsylvania, USA.
FAU - Cox, Donna S
AU  - Cox DS
AD  - Teva Branded Pharmaceutical Products R&D Inc, West Chester, Pennsylvania, USA.
FAU - Levi, Micha
AU  - Levi M
AD  - Teva Branded Pharmaceutical Products R&D Inc, West Chester, Pennsylvania, USA.
FAU - Garin, Margaret
AU  - Garin M
AD  - Teva Branded Pharmaceutical Products R&D Inc, West Chester, Pennsylvania, USA.
FAU - Fiedler-Kelly, Jill
AU  - Fiedler-Kelly J
AD  - Cognigen Corporation, a Simulations Plus company, Buffalo, New York, USA.
FAU - Bond, Mary
AU  - Bond M
AD  - Teva Branded Pharmaceutical Products R&D Inc, West Chester, Pennsylvania, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200425
PL  - England
TA  - J Clin Pharmacol
JT  - Journal of clinical pharmacology
JID - 0366372
RN  - 0 (Anti-Asthmatic Agents)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 35A26E427H (reslizumab)
SB  - IM
MH  - Administration, Intravenous
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Anti-Asthmatic Agents/administration & dosage/adverse 
      effects/pharmacokinetics/*pharmacology
MH  - Antibodies, Monoclonal, Humanized/administration & dosage/adverse 
      effects/pharmacokinetics/*pharmacology
MH  - Asthma/drug therapy
MH  - Bayes Theorem
MH  - Body Weight
MH  - Child
MH  - Clinical Trials as Topic
MH  - Computer Simulation
MH  - Dose-Response Relationship, Drug
MH  - Drug Administration Schedule
MH  - Eosinophils/drug effects
MH  - Female
MH  - Forced Expiratory Volume/drug effects
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Models, Biological
MH  - Muscular Diseases/chemically induced
MH  - Young Adult
OTO - NOTNLM
OT  - exposure
OT  - exposure-response eosinophilic asthma
OT  - modeling
OT  - pharmacodynamic
OT  - pharmacokinetic
OT  - reslizumab
EDAT- 2020/04/26 06:00
MHDA- 2021/07/10 06:00
CRDT- 2020/04/26 06:00
PHST- 2019/10/04 00:00 [received]
PHST- 2020/02/25 00:00 [accepted]
PHST- 2020/04/26 06:00 [pubmed]
PHST- 2021/07/10 06:00 [medline]
PHST- 2020/04/26 06:00 [entrez]
AID - 10.1002/jcph.1609 [doi]
PST - ppublish
SO  - J Clin Pharmacol. 2020 Aug;60(8):1039-1050. doi: 10.1002/jcph.1609. Epub 2020 Apr 
      25.