title: Population pharmacokinetic modelling of irosustat in postmenopausal women with oestrogen-receptor positive breast cancer incorporating non-linear red blood cell uptake.
abstract: OBJECTIVE
  Irosustat is the 'first-in-class' irreversible potent steroid sulphatase inhibitor with lack of oestrogenic activity. The objective of this work was to develop a population model characterizing simultaneously the pharmacokinetic profiles of irosustat in plasma and whole blood.
  
  
  METHODS
  This clinical study was an open label, multicentre, phase I multiple cohort dose escalation trial conducted in 35 postmenopausal women with oestrogen-receptor positive breast cancer. Patients received 1, 5, 20, 40, or 80 mg oral doses. Irosustat was administered as a single oral dose to each patient followed by an observation period of 7 days. On day 8 each patient received once daily oral administration until day 34. Concentrations of irosustat in both blood and plasma were obtained and pharmacokinetic analyses were performed with NONMEM 7.2.
  
  
  CONCLUSIONS
  Irosustat showed non-linear disposition characteristics modelled as maximum binding capacity into the red blood cells. Plasma concentration corresponding to half of the maximum capacity was 32.79 ng/mL. The value of the blood to plasma concentration ratio in linear conditions was 419, indicating very high affinity for the red blood cells. Apparent plasma and blood clearances were estimated in 1199.52 and 3.90 L/day, respectively. Pharmacokinetics of irosustat showed low-moderate inter-subject variability, and neither the demographics (e.g., age, or weight) nor the phenotypes for CYP2C9, CYP2C19, and CYP3A5 enzymes showed statistically significant effects. Relative bioavailability was decreased as the administered dose was augmented. The model predicted a 47% decrease in relative bioavailability in the 40 mg with respect to the 1 mg dose.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, 31080, Spain.
authors.forename: Zinnia P
authors.initials: ZP
authors.lastname: Parra-Guillen
authors.forename: Josep María
authors.initials: JM
authors.lastname: Cendrós Carreras
authors.forename: Concepción
authors.initials: C
authors.lastname: Peraire
authors.forename: Rosendo
authors.initials: R
authors.lastname: Obach
authors.forename: Joan
authors.initials: J
authors.lastname: Prunynosa
authors.forename: Eric
authors.initials: E
authors.lastname: Chetaille
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Trocóniz
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000378:metabolism*; D013451:Sulfonic Acids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D013451:Sulfonic Acids; C520511:irosustat