title: Population pharmacokinetic analysis of sifalimumab from a clinical phase IIb trial in systemic lupus erythematosus patients.
abstract: OBJECTIVE
  Sifalimumab, a human immunoglobulin (Ig) G1 monoclonal antibody against INF-alpha, is being studied as a treatment for systemic lupus erythematosus (SLE). This analysis characterized population pharmacokinetics (PK) of sifalimumab following repeat fixed dose and evaluated the utility of fixed dosing vs. body weight normalized dosing in SLE patients.
  
  
  METHODS
  PK data were collected in a phase IIb study where 298 patients received multiple intravenous doses (200-1200 mg) of sifalimumab every 4 weeks for 52 weeks. A population pharmacokinetic model was developed using 3961 quantifiable serum concentrations and the impact of patient demographics, clinical indices and biomarkers on pharmacokinetic parameters was evaluated. The appropriateness of the final model was evaluated using visual predictive check and bootstrap.
  
  
  RESULTS
  A two compartment model with first order elimination adequately described sifalimumab serum PK. The estimated typical clearance (CL) and central volume of distribution (V1 ) were 184 ml day(-1) and 2.82 l with 24% and 16% between-subject variability (BSV), respectively. Body weight, dose, 21 INF gene signature baseline and concomitant steroid use were identified as statistically significant covariates for CL and V1 and accounted for <10% of PK variability in the final model. Typical values and BSV of PK parameters from the current analysis with fixed dosing were similar to previous population PK results with body weight normalized dosing.
  
  
  CONCLUSIONS
  The transition from body weight normalized dosing to fixed dosing did not impact sifalimumab PK. These findings support the use of fixed dosing for sifalimumab in future clinical studies evaluating it as a potential treatment for SLE.
authors.affiliation: Clinical Pharmacology and DMPK (CPD), MedImmune, LLC, One MedImmune Way, Gaithersburg, Maryland, 20878.
authors.forename: Bo
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Clinical Pharmacology and DMPK (CPD), MedImmune, LLC, One MedImmune Way, Gaithersburg, Maryland, 20878.
authors.forename: Xiang-Qing
authors.initials: XQ
authors.lastname: Yu
authors.affiliation: Clinical Development, MedImmune, LLC, One MedImmune Way, Gaithersburg, Maryland, 20878, USA.
authors.forename: Warren
authors.initials: W
authors.lastname: Greth
authors.affiliation: Clinical Pharmacology and DMPK (CPD), MedImmune, LLC, One MedImmune Way, Gaithersburg, Maryland, 20878.
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Robbie
mesh_terms: D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D001835:Body Weight; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D012737:Sex Factors; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C568334:sifalimumab
keywords: clinical trial; population pharmacokinetic modelling; sifalimumab; systemic lupus erythematosus