title: Population PK and IgE pharmacodynamic analysis of a fully human monoclonal antibody against IL4 receptor.
abstract: OBJECTIVE
  For AMG 317, a fully human monoclonal antibody to interleukin receptor IL-4Rα, we developed a population pharmacokinetic (PK) model by fitting data from four early phase clinical trials of intravenous and subcutaneous (SC) routes simultaneously, investigated important PK covariates, and explored the relationship between exposure and IgE response.
  
  
  METHODS
  Data for 294 subjects and 2183 AMG 317 plasma concentrations from three Phase 1 and 1 Phase 2 studies were analyzed by nonlinear mixed effects modeling using first-order conditional estimation with interaction. The relationship of IgE response with post hoc estimates of exposure generated from the final PK model was explored based on data from asthmatic patients.
  
  
  RESULTS
  The best structural model was a two-compartment quasi-steady-state target-mediated drug disposition model with linear and non-linear clearances. For a typical 80-kg, 40-year subject, linear clearance was 35.0 mL/hr, central and peripheral volumes of distribution were 1.78 and 5.03 L, respectively, and SC bioavailability was 24.3%. Body weight was an important covariate on linear clearance and central volume; age influenced absorption rate. A significant treatment effect was observable between the cumulative AUC and IgE response measured.
  
  
  CONCLUSIONS
  The population PK model adequately described AMG 317 PK from IV and SC routes over a 60-fold range of doses with two dosing strengths across multiple studies covering healthy volunteers and patients with mild to severe asthma. IgE response across a range of doses and over the sampling time points was found to be related to cumulative AMG 317 exposure.
authors: Department of Pharmacokinetics and Metabolism, Amgen Inc., Thousand Oaks, California, 91320, USA. tkakkar@amgen.com
authors: Tarundeep
authors: T
authors: Kakkar
authors: Cynthia
authors: C
authors: Sung
authors: Leonid
authors: L
authors: Gibiansky
authors: Thuy
authors: T
authors: Vu
authors: Adimoolam
authors: A
authors: Narayanan
authors: Shao-Lee
authors: SL
authors: Lin
authors: Michael
authors: M
authors: Vincent
authors: Christopher
authors: C
authors: Banfield
authors: Alex
authors: A
authors: Colbert
authors: Sarah
authors: S
authors: Hoofring
authors: Marta
authors: M
authors: Starcevic
authors: Peiming
authors: P
authors: Ma
references: BMC Pulm Med. 2010 Jan 08;10:3
references: 20064211
references: J Immunol. 2004 Apr 1;172(7):4545-55
references: 15034072
references: Science. 1998 Dec 18;282(5397):2258-61
references: 9856949
references: J Clin Pharmacol. 2008 Mar;48(3):267-78
references: 18218786
references: J Clin Pharmacol. 2009 Oct;49(10):1142-56
references: 19723673
references: J Allergy Clin Immunol. 2000 Mar;105(3):506-13
references: 10719301
references: J Pharmacokinet Pharmacodyn. 2008 Oct;35(5):573-91
references: 19005743
references: Clin Chest Med. 2006 Mar;27(1):133-47, vii
references: 16543058
references: AAPS J. 2009 Sep;11(3):558-69
references: 19649712
references: J Immunol. 2000 Jul 1;165(1):108-13
references: 10861042
references: Pharm Res. 2008 Feb;25(2):359-68
references: 17587152
references: J Clin Pharmacol. 2007 Mar;47(3):383-96
references: 17322150
references: J Clin Pharmacol. 2005 Apr;45(4):468-76
references: 15778428
references: Genes Immun. 1999 Sep;1(1):61-5
references: 11197307
references: Drug Metab Rev. 1984;15(5-6):1071-121
references: 6396053
references: Cancer Chemother Pharmacol. 2005 Oct;56(4):361-9
references: 15868146
references: Comput Methods Programs Biomed. 1999 Apr;59(1):19-29
references: 10215174
references: Proc Natl Acad Sci U S A. 1977 Jul;74(7):2993-7
references: 70786
references: Science. 1998 Dec 18;282(5397):2261-3
references: 9856950
references: Br J Clin Pharmacol. 2007 May;63(5):548-61
references: 17096680
references: N Engl J Med. 1997 Dec 11;337(24):1720-5
references: 9392697
references: Allergy. 2005 Mar;60(3):309-16
references: 15679715
references: Pharm Res. 2009 Dec;26(12):2543-50
references: 19847627
references: Cancer Metastasis Rev. 1990 Nov;9(3):253-66
references: 2292138
references: Pharm Res. 1991 Nov;8(11):1351-9
references: 1798669
references: Blood. 2000 Sep 15;96(6):2172-80
references: 10979963
references: Am J Respir Crit Care Med. 2010 Apr 15;181(8):788-96
references: 20056900
references: J Clin Pharmacol. 2009 Sep;49(9):1025-36
references: 19717725
references: J Clin Pharmacol. 2008 Jun;48(6):681-95
references: 18401017