title: Population PK/PD modeling of eltrombopag in subjects with advanced solid tumors with chemotherapy-induced thrombocytopenia.
abstract: OBJECTIVE
  Eltrombopag, a thrombopoietin receptor agonist, is being evaluated for the treatment of chemotherapy-induced thrombocytopenia. Due to the delay in platelet response after the administration of eltrombopag or chemotherapy, a modeling and simulation approach was used to optimize the eltrombopag dosing regimen.
  
  
  METHODS
  Pharmacokinetic (PK) data from 2 studies in healthy subjects and PK and platelet data from a Phase II study in subjects with cancer receiving carboplatin/paclitaxel (where eltrombopag was given 10 days after chemotherapy) were used to develop a nonlinear mixed-effects PK/PD model. Alternative eltrombopag dosing regimens were then simulated.
  
  
  RESULTS
  The PK model was a linear two-compartment model with first-order absorption. Being Asian, female, and >50 years of age were associated with higher eltrombopag exposure. The time course of platelet counts was described by a four-compartment transit model. Carboplatin inhibited platelet precursor production linearly with dose, with increased effect with each cycle of chemotherapy. Eltrombopag stimulated platelet precursor production, proportional to plasma eltrombopag concentration, and stimulation (slope of the concentration effect) was attenuated with each cycle of chemotherapy.
  
  
  CONCLUSIONS
  Simulations indicated that eltrombopag administered 5 days before and 5 days after chemotherapy minimizes the decrease and fluctuations in platelet counts relative to other evaluated dosing regimens.
authors.affiliation: ICON Development Solutions, Marlow, Buckinghamshire, UK.
authors.forename: Siobhan
authors.initials: S
authors.lastname: Hayes
authors.forename: Paul N
authors.initials: PN
authors.lastname: Mudd
authors.forename: Daniele
authors.initials: D
authors.lastname: Ouellet
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Johnson
authors.forename: Daphne
authors.initials: D
authors.lastname: Williams
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Gibiansky
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001565:Benzoates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D053628:Receptors, Thrombopoietin / Q000819:agonists*; D013921:Thrombocytopenia / Q000139:chemically induced / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C520809:eltrombopag