title: Population pharmacokinetic modelling of Emfilermin (recombinant human leukaemia inhibitory factor, r-hLIF) in healthy postmenopausal women and in infertile patients undergoing in vitro fertilization and embryo transfer.
abstract: OBJECTIVE
  The aim of this analysis was to develop a population pharmacokinetic model for Emfilermin (recombinant human leukaemia inhibitory factor, r-hLIF) following subcutaneous administration to healthy postmenopausal women and to infertile patients undergoing in vitro fertilization and embryo transfer (IVF-ET).
  
  
  METHODS
  Data from three studies, a single and a repeat dose Phase I study in postmenopausal women as well as a proof of concept study in patients undergoing in vitro fertilization and embryo transfer were combined and analyzed. The structural pharmacokinetic model was developed using the rich data from the Phase I studies and the full pharmacostatistical model was then derived using all the data.
  
  
  RESULTS
  The pharmacokinetics of r-hLIF after repeated subcutaneous administration were described by a one-compartment disposition model with a zero order input. The duration of the absorption phase was short (0.8 h) and invariant. The apparent clearance in postmenopausal women was 57 l h(-1) (CV = 17%). In in vitro fertilization and embryo transfer patients, the apparent clearance was decreased by 35% compared with postmenopausal women. The apparent volume of distribution was 235 l (interindividual CV = 28%) and exhibited an interoccasion variability of 23%. It increased (for weight above 62 kg) or decreased (for weight below 62 kg) by 29% for every 10 kg body weight. The median posthoc estimates of apparent clearance and volume of distribution and their variability were consistent with the population estimates. In postmenopausal women, the results were consistent with those obtained by noncompartmental analysis. The residual variability on r-hLIF serum concentrations was 20%.
  
  
  CONCLUSIONS
  The pharmacokinetics of r-hLIF after repeated SC administration were described by a one compartment disposition model, with zero order input, in postmenopausal women and those undergoing IVF or intracytoplasmic sperm injection and embryo transfer. Absorption of r-hLIF was rapid as was its subsequent clearance. The apparent volume of distribution of r-hLIF was moderate to high, depended on body weight and showed interoccasion variability.
authors.affiliation: Human Pharmacology Group, Serono International S.A., 12 Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland.
authors.forename: Timothy
authors.initials: T
authors.lastname: Goggin
authors.forename: Quyen T X
authors.initials: QT
authors.lastname: Nguyen
authors.forename: Alain
authors.initials: A
authors.lastname: Munafo
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D000368:Aged; D004624:Embryo Transfer; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005307:Fertilization in Vitro / Q000379:methods; D006801:Humans; D007247:Infertility, Female / Q000188:drug therapy / Q000378:metabolism*; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008875:Middle Aged; D008954:Models, Biological; D017698:Postmenopause / Q000378:metabolism*; D011506:Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000493:pharmacokinetics
chemical_list: D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D011506:Proteins; D011994:Recombinant Proteins