title: Population pharmacokinetics of tanezumab in phase 3 clinical trials for osteoarthritis pain.
abstract: OBJECTIVE
  The aims were to 1) develop the pharmacokinetics model to describe and predict observed tanezumab concentrations over time, 2) test possible covariate parameter relationships that could influence clearance and distribution and 3) assess the impact of fixed dosing vs. a dosing regimen adjusted by body weight.
  
  
  METHODS
  Individual concentration-time data were determined from 1608 patients in four phase 3 studies conducted to assess efficacy and safety of intravenous tanezumab. Patients received two or three intravenous doses (2.5, 5 or 10 mg) every 8 weeks. Blood samples for assessment of tanezumab PK were collected at baseline, 1 h post-dose and at weeks 4, 8, 16 and 24 (or early termination) in all studies. Blood samples were collected at week 32 in two studies. Plasma samples were analyzed using a sensitive, specific, validated enzyme-linked immunosorbent assay.
  
  
  RESULTS
  A two compartment model with parallel linear and non-linear elimination processes adequately described the data. Population estimates for clearance (CL), central volume (V1 ), peripheral volume (V2 ), inter-compartmental clearance, maximum elimination capacity (VM) and concentration at half-maximum elimination capacity were 0.135 l day(-1) , 2.71 l, 1.98 l, 0.371 l day(-1) , 8.03 μg day(-1) and 27.7 ng ml(-1) , respectively. Inter-individual variability (IIV) was included on CL, V1 , V2 and VM. A mixture model accounted for the distribution of residual error. While gender, dose and creatinine clearance were significant covariates, only body weight as a covariate of CL, V1 and V2 significantly reduced IIV.
  
  
  CONCLUSIONS
  The small increase in variability associated with fixed dosing is consistent with other monoclonal antibodies and does not change risk : benefit.
authors.affiliation: Pharmetheus AB, Uppsala, Sweden.
authors.forename: E Niclas
authors.initials: EN
authors.lastname: Jonsson
authors.affiliation: Pfizer Ltd., Shanghai, China.
authors.forename: Rujia
authors.initials: R
authors.lastname: Xie
authors.affiliation: Pfizer Ltd., Sandwich, UK and.
authors.forename: Scott F
authors.initials: SF
authors.lastname: Marshall
authors.affiliation: Pfizer Inc, Groton, CT, USA.
authors.forename: Rosalin H
authors.initials: RH
authors.lastname: Arends
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001835:Body Weight; D059350:Chronic Pain / Q000097:blood / Q000188:drug therapy*; D017326:Clinical Trials, Phase III as Topic; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010003:Osteoarthritis / Q000097:blood / Q000188:drug therapy*; D011237:Predictive Value of Tests; D020800:Receptor, Nerve Growth Factor / Q000037:antagonists & inhibitors; D014018:Tissue Distribution
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D020800:Receptor, Nerve Growth Factor; C549319:tanezumab
keywords: population pharmacokinetics; tanezumab