title: Population pharmacokinetics and pharmacodynamics of linezolid-induced thrombocytopenia in hospitalized patients.
abstract: Thrombocytopenia is among the most important adverse effects of linezolid treatment. Linezolid-induced thrombocytopenia incidence varies considerably but has been associated with impaired renal function. We investigated the pharmacodynamic mechanism (myelosuppression or enhanced platelet destruction) and the role of impaired renal function (RF) in the development of thrombocytopenia.
  
  
  
  The pharmacokinetics of linezolid were described with a two-compartment distribution model with first-order absorption and elimination. RF was calculated using the expected creatinine clearance. The decrease platelets by linezolid exposure was assumed to occur by one of two mechanisms: inhibition of the formation of platelets (PDI) or stimulation of the elimination (PDS) of platelets.
  
  
  
  About 50% of elimination was found to be explained by renal clearance (normal RF). The population mean estimated plasma protein binding of linezolid was 18% [95% confidence interval (CI) 16%, 20%] and was independent of the observed concentrations. The estimated mixture model fraction of patients with a platelet count decreased due to PDI was 0.97 (95% CI 0.87, 1.00), so the fraction due to PDS was 0.03. RF had no influence on linezolid pharmacodynamics.
  
  
  
  We have described the influence of weight, renal function, age and plasma protein binding on the pharmacokinetics of linezolid. This combined pharmacokinetic, pharmacodynamic and turnover model identified that the most common mechanism of thrombocytopenia associated with linezolid is PDI. Impaired RF increases thrombocytopenia by a pharmacokinetic mechanism. The linezolid dose should be reduced in RF.
authors.affiliation: Department of Medical Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan.|Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsuji
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand.
authors.forename: Nicholas H G
authors.initials: NHG
authors.lastname: Holford
authors.affiliation: Department of Medical Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan.|Certara G.K., Tokyo, Japan.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Kasai
authors.affiliation: Department of Medical Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Chika
authors.initials: C
authors.lastname: Ogami
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand.
authors.forename: Young-A
authors.initials: YA
authors.lastname: Heo
authors.affiliation: Department of Clinical Infectious Diseases, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Higashi
authors.affiliation: Department of Pharmacy, Sasebo Chuo Hospital, Nagasaki, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Mizoguchi
authors.affiliation: Department of Medical Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: To
authors.affiliation: Department of Clinical Infectious Diseases, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamamoto
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects*; D001853:Bone Marrow / Q000187:drug effects*; D002648:Child; D003404:Creatinine / Q000097:blood / Q000652:urine; D003428:Cross Infection; D005260:Female; D006801:Humans; D015994:Incidence; D007677:Kidney Function Tests; D007902:Length of Stay; D000069349:Linezolid / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008657:Metabolic Clearance Rate; D055624:Methicillin-Resistant Staphylococcus aureus / Q000302:isolation & purification; D008875:Middle Aged; D010976:Platelet Count; D051437:Renal Insufficiency / Q000097:blood / Q000150:complications / Q000652:urine; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013921:Thrombocytopenia / Q000097:blood / Q000453:epidemiology* / Q000209:etiology / Q000652:urine; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D003404:Creatinine; D000069349:Linezolid
keywords: linezolid; methicillin-resistant Staphylococcus aureus; mixture model; pharmacometrics; thrombocytopenia; turnover model