ORIGINAL RESEARCH ARTICLE

• Published in: Clinical pharmacokinetics Vol. 58; no. 11; pp. 1469 - 1482
• Main Authors: Katsube, Takayuki, Shimizu, Ryosuke, Fukuhara, Takahiro, Kano, Takeshi, Wajima, Toshihiro
• Format: Journal Article
• Language: English
• Published: Auckland Springer Nature B.V 01.11.2019
• Subjects: Bioavailability; Blood platelets; Creatinine; Ethnicity; Food; Liver cirrhosis; Liver diseases; Pharmacodynamics; Pharmacokinetics; Plasma; Population; Signal transduction; Simulation; Thrombocytopenia; Values; Japan
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-019-00770-4

Platelet transfusion is the current standard of care to reduce bleeding risk in these patients; however, platelet transfusion has complications, including risk of allergic and febrile nonhaemolytic transfusion reactions, refractoriness, and infection, as well as treatment limitations such as unpredictable increases in haemostatic platelet levels, short duration of effect, and requirement for hospitalization [2, 3]. In a clinical study of another TPO-RA- eltrombopag-in patients with cirrhosis and severe thrombocytopenia, the risk of thrombotic events increased above a platelet count of 200,000/pL, although the causality has not been established [7]. [...]the therapeutic window of platelet counts is considered to be 50,000-200,000/pL for the treatment of thrombocytopenia in CLD patients, which is relatively narrow given that the haemostatic balance in CLD patients is known to be fragile and the patients may easily become either hypoor hypercoagulable [8]. PK parameters were estimated from data in both healthy subjects and patients with CLD. Since the bioavailability of lusutrombopag was dependent on formulations and food conditions [9], a relative bioavailability, F1, was parameterized for the formulation (solution, 0.25 mg, 1 mg, 2 mg, or 3 mg tablet) in the food condition (fasted or fed). In the covariate modelling, the following effects were tested: age, body weight, sex, Child-Pugh classification (A, B or C) [13], creatinine clearance estimated using the Cockcroft-Gault equation [14], ethnicity (Japanese or non-Japanese subjects), and subject population (healthy subjects or CLD patients) on CL/F; age, body weight, sex, ethnicity, and subject population on V2/F; and body weight on V3/F.