title: Romiplostim dose response in patients with immune thrombocytopenia.
abstract: A pharmacodynamic model was developed for platelet counts in 52 patients with immune thrombocytopenia (ITP) receiving subcutaneous romiplostim in 3 phase I/II studies (dose range, 0.2-10 µg/kg). The model consisted of a drug-sensitive progenitor cell compartment linked to a peripheral blood compartment through 4 transition compartments. The baseline platelet count, mean transit time, and kinetics of drug effect constant were 11.1 × 10(9)/L, 170 hours, and 0.6 day(-1), respectively. The ITP patients had a shorter platelet life span and lower progenitor cell production rates than healthy volunteers. Romiplostim response was described for 2 subpopulations. The romiplostim stimulatory effect in ITP patients was 351%/100 µg/wk and 12%/100 µg/wk in 68% and 32% of patients, respectively. Visual and numerical predictive checks suggested accurate prediction of platelet time course and durable response rate in ITP patients. Model-based simulations confirmed the effectiveness of dose reduction to prevent platelet counts >400 × 10(9)/L.
authors.affiliation: Amgen SA, Barcelona, Spain. juanjose@amgen.com
authors.forename: J J
authors.initials: JJ
authors.lastname: Perez-Ruixo
authors.forename: B
authors.initials: B
authors.lastname: Green
authors.forename: S
authors.initials: S
authors.lastname: Doshi
authors.forename: Y-M
authors.initials: YM
authors.lastname: Wang
authors.forename: D R
authors.initials: DR
authors.lastname: Mould
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000097:blood*; D011961:Receptors, Fc / Q000008:administration & dosage*; D053628:Receptors, Thrombopoietin / Q000819:agonists*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D013926:Thrombopoietin / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D011961:Receptors, Fc; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; D013926:Thrombopoietin; C488777:romiplostim