Population Pharmacokinetic and Pharmacodynamic Modeling and Effects on Platelet Counts of Different Dosages of Eltrombopag in Chinese Patients With Chronic Primary Immune Thrombocytopenia.
OBJECTIVE
This study characterized the population pharmacokinetic (pop-PK) and PK/pharmacodynamic (pop-PK/PD) properties of eltrombopag and evaluated platelet count (PLTC) response to different eltrombopag dosages through simulations in Chinese adult patients with chronic primary immune thrombocytopenia (cITP).


METHODS
Pop-PK and pop-PK/PD models were developed from Chinese patients with cITP. Model-based simulations were then performed to predict PLTC response.


RESULTS
The pop-PK properties of eltrombopag were described by a 2-compartment model with first-order absorption and elimination and absorption lag time. Steady-state exposure in these Chinese patients was ~55% greater than that in non-East Asian patients. The pop-PK/PD properties of eltrombopag were described by a model with 4 transit compartments where the increase in platelet production rate was linearly related to the plasma eltrombopag concentration. Eleven percent of the patients were identified as nonresponders to eltrombopag. Simulations showed that ~70% to 80% of steady-state PLTC response was achieved at week 2, and the percentages of patients who achieved a PLTC of 50 to 150 × 10(9) cells/L were comparable between weeks 2 and 6 with 12.5-, 25-, 50-, and 75-mg once-daily dosing. The 25-mg once-daily dosage was associated with a more balanced response than were the 12.5-, 50-, and 75-mg once-daily dosages with regard to efficacy (percentages of patients with PLTC 50-150 × 10(9) cells/L, 27% vs 20%, 30%, and 30%, respectively) and the risk for thrombocytosis (percentages of patients with PLTC >250 × 10(9) cells/L, 4% vs 1%, 10%, and 16%). Simulations of PLTCs with the dose-titration regimen showed that ≥42% of patients achieved a PLTC 50 to 150 × 10(9) cells/L at week 6 or later, compared with ≤30% when the 12.5-, 25-, 50-, and 75-mg once-daily fixed doses were given. No more than 5% of patients who underwent dose titration had a PLTC >250 × 10(9) cells/L throughout 24 weeks of treatment, compared with 3%, 7%, 16%, and 24% when the once-daily fixed doses of eltrombopag were given.


CONCLUSIONS
The pop-PK and pop-PK/PD properties of eltrombopag in these Chinese adult patients with cITP were adequately characterized in the present analyses. The modeling and simulation results support the eltrombopag dose-titration regimen, with 25 mg once daily as a starting dosage and a 2-week titration interval, in Chinese patients with cITP.
Department of Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, Shanghai, China.
Kai
K
Wu
ICON Development Solutions, Marlow, United Kingdom.
Mita
M
Thapar
ICON Development Solutions, Marlow, United Kingdom.
Colm
C
Farrell
ICON Development Solutions, Marlow, United Kingdom.
Siobhan
S
Hayes
China Medicine Development, GlaxoSmithKline, Shanghai, China.
Haiyi
H
Guo
Department of Hematology, Qilu Hospital, Shandong University, Shandong, China. Electronic address: houming@medmail.com.cn.
Ming
M
Hou
Department of Clinical Pharmacology, Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, North Carolina.
Jianping
J
Zhang
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People; D001565:Benzoates / Q000008:administration & dosage / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects*; D002681:China; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000097:blood / Q000188:drug therapy*; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D053628:Receptors, Thrombopoietin / Q000819:agonists*; D055815:Young Adult
D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; C520809:eltrombopag
Chinese; eltrombopag; immune thrombocytopenia; platelet count; population pharmacokinetics/pharmacodynamics