title: Pharmacokinetic-pharmacodynamic analysis of sunitinib-induced thrombocytopenia in Japanese patients with renal cell carcinoma.
abstract: The aim of the present study was to clarify the therapeutic range and adequate dose of sunitinib in Japanese renal cell carcinoma patients by means of a pharmacokinetic-pharmacodynamic analysis of sunitinib-induced thrombocytopenia. Six patients with renal cell carcinoma were enrolled in this study. After starting the sunitinib treatment, between three and seven blood samples were obtained from each patient just before the administration of sunitinib. Serum concentrations of sunitinib and its active metabolite N-desethyl-sunitinib were fit to the 1-compartment model with first-order absorption. Changes in platelet counts were fit to the pharmacokinetic-pharmacodynamic model, in which the proliferation of platelet progenitor cells was assumed to be linearly inhibited by sunitinib and its metabolite. All patients using 50 mg as an initial dose of sunitinib developed grade 2 or 3 thrombocytopenia. The pharmacokinetic-pharmacodynamic model created successfully described the time course of sunitinib-induced thrombocytopenia and could predict changes in platelet counts after alterations to the dosage of sunitinib administered. The simulation results indicated that the total trough level of sunitinib to avoid severe thrombocytopenia should be <100 ng/mL, and also that the initial daily dose of sunitinib could be reduced to 37.5 mg or 25 mg in most Japanese patients. In addition to the pharmacokinetic-guided dosage adjustment, the careful monitoring of platelet counts is required for the safe use of sunitinib.
authors.affiliation: Department of Pharmacy, Medical Hospital, Tokyo Medical and Dental University.
authors.forename: Masashi
authors.initials: M
authors.lastname: Nagata
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Ishiwata
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Takahashi
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Saito
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fujii
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kihara
authors.forename: Masato
authors.initials: M
authors.lastname: Yasuhara
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D044466:Asian People; D001792:Blood Platelets / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D007408:Intestinal Absorption; D007564:Japan; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010976:Platelet Count; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077210:Sunitinib; D013921:Thrombocytopenia / Q000209:etiology / Q000517:prevention & control*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib