title: Accounting for Pharmacokinetic Variability of Certolizumab Pegol in Patients with Crohn's Disease.
abstract: Certolizumab pegol is an effective biologic for patients with Crohn's disease (CD). Individual differences in certolizumab pegol apparent clearance (CL/F) affect exposure and possibly efficacy. A previously developed population pharmacokinetic (PK) model did not account for dynamic changes in clinical parameters during therapy.
  
  
  
  The aim of this study was to refine the existing PK model to capture the time-varying influence of covariates.
  
  
  
  Data collected from 2157 Crohn's disease patients in nine studies were analyzed using nonlinear mixed-effects modeling software (NONMEM). Certolizumab pegol concentration-time data were described by a one-compartment PK model with first-order absorption, and one-compartment disposition with linear, time-dependent elimination using antidrug antibody (ADAb) concentration as a continuous variable.
  
  
  
  The final dataset consisted of 12,926 analyzable records. Parameter estimates were absorption rate constant 1.83/day, CL/F 0.527 L/day, and apparent volume of distribution (V/F) 8.33 L. ADAb concentration (2.5-214 units/mL) increased the median CL/F by 142-174%. For a typical patient, body weight (46.8-100.5 kg) increased the median CL/F and V/F from 82 to 120%. Albumin (32-48 g/L) decreased and C-reactive protein (0.5-54.0 mg/L) increased the median CL/F from 123 to 85% and from 83 to 113%, respectively. Between-patient variability of CL/F was 19.6%.
  
  
  
  By incorporating time-varying covariates, this population PK model reduces between-patient variability on CL/F estimates, and the relative influence of ADAb can now be assessed. As Crohn's disease patient covariates are often time-dependent, this model is more reflective of patient drug exposure with sustained treatment.
authors.affiliation: Division of Gastroenterology, School of Medicine, IBD Center, University of California San Diego, 9500 Gilman Drive #0956, La Jolla, CA, 92093, USA. nvandecasteele@ucsd.edu.|Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Louvain, Belgium. nvandecasteele@ucsd.edu.|Robarts Research Institute, London, ON, Canada. nvandecasteele@ucsd.edu.
authors.forename: Niels
authors.initials: N
authors.lastname: Vande Casteele
authors.affiliation: Projections Research Inc., Phoenixville, PA, USA.
authors.forename: Diane R
authors.initials: DR
authors.lastname: Mould
authors.affiliation: UCB Pharma, Raleigh, NC, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Coarse
authors.affiliation: UCB Pharma, Raleigh, NC, USA.
authors.forename: Iram
authors.initials: I
authors.lastname: Hasan
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Louvain, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Gils
authors.affiliation: Robarts Research Institute, London, ON, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Feagan
authors.affiliation: Division of Gastroenterology, School of Medicine, IBD Center, University of California San Diego, 9500 Gilman Drive #0956, La Jolla, CA, 92093, USA.|Robarts Research Institute, London, ON, Canada.
authors.forename: William J
authors.initials: WJ
authors.lastname: Sandborn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000276:immunology; D002097:C-Reactive Protein / Q000378:metabolism; D000068582:Certolizumab Pegol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002986:Clinical Trials as Topic; D003424:Crohn Disease / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D000075462:Serum Albumin, Human / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000906:Antibodies; D007166:Immunosuppressive Agents; D002097:C-Reactive Protein; D000068582:Certolizumab Pegol; D000075462:Serum Albumin, Human