Romiplostim dose response in patients with immune thrombocytopenia |
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Authors: | Perez-Ruixo J J Green B Doshi S Wang Y-M Mould D R |
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Affiliation: | Department of Pharmacokinetics and Drug Metabolism, Picayo, 3 Puzol (46530), Valencia, Spain; e-mail: juanjose@amgen.com. |
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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. |
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