title: Population pharmacokinetic/pharmacodynamic modelling of the anti-TNF-α polyclonal fragment antibody AZD9773 in patients with severe sepsis.
abstract: AZD9773 is an ovine-derived, polyclonal, anti-tumour necrosis factor-alpha (TNF-α) antibody fragment. Using data from an AZD9773 Phase IIa study in patients with severe sepsis (clinicaltrials.gov: NCT00615017), a population pharmacokinetic/pharmacodynamic (PK/PD) model was developed. The model assessed the influence of various covariates on the PK of AZD9773 and the relationship between AZD9773 exposure and serological TNF-α concentration. A linear two-compartment model was used to describe AZD9773 concentration-time data. A stepwise covariate analysis was performed on the PK parameters. Subsequently, the serological TNF-α concentrations and drug effect were captured using an indirect response model, with a variable production rate of TNF-α described by a quadratic function. Creatinine clearance (CrCL) was the only covariate with a significant effect on the PK of AZD9773. A typical patient's drug clearance varied with CrCL; the relationship was non-linear. Diagnostic analysis of the PK/PD model showed that the fit was good, both across cohorts and in AZD9773-treated versus placebo patients. Serological TNF-α concentrations and the reduction of measurable serum TNF-α by AZD9773 were well characterized across all the cohorts evaluated in the Phase IIa study. This population PK/PD model was subsequently used to simulate alternative dosing options for a Phase IIb study (clinicaltrials.gov: NCT01145560).
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. james.yates@astrazeneca.com
authors.forename: James W T
authors.initials: JW
authors.lastname: Yates
authors.forename: Shampa
authors.initials: S
authors.lastname: Das
authors.forename: Guy
authors.initials: G
authors.lastname: Mainwaring
authors.forename: John
authors.initials: J
authors.lastname: Kemp
mesh_terms: D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000378:metabolism*; D008954:Models, Biological; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D007140:Immunoglobulin Fab Fragments; D014409:Tumor Necrosis Factor-alpha