title: Analysis of thrombocytopenic effects and population pharmacokinetics of linezolid: a dosage strategy according to the trough concentration target and renal function in adult patients.
abstract: The pharmacokinetic/pharmacodynamic (PK/PD) index for the efficacy of linezolid is a 24-h area under the plasma drug concentration-time curve (AUC₂₄)/minimum inhibitory concentration (MIC) ratio of ≥100. The main adverse event associated with administration of linezolid is thrombocytopenia. Therefore, the aims of the present study were to define PD thresholds that would minimise linezolid-induced thrombocytopenia and to perform a population PK analysis to identify factors influencing the pharmacokinetics of linezolid. Population PK analysis revealed that creatinine clearance (CLCr) significantly affected linezolid pharmacokinetics: the mean parameter estimate of drug clearance (CL; in L/h)=0.0258 × CLCr + 2.03. A strong correlation (r=0.970) was found between AUC₂₄ and trough plasma concentrations (Cmin) [AUC₂₄=18.2 × Cmin + 134.4]. The Cmin value for AUC₂₄=200 (in the case of MIC=2 μg/mL) was estimated to be 3.6 μg/mL. Regarding safety, Cmin was a significant predictor of thrombocytopenia during treatment, and its threshold to minimise linezolid-induced thrombocytopenia was 8.2 μg/mL. A Kaplan-Meier plot revealed that the median time from initiation of therapy to the development of thrombocytopenia was 15 days. Therefore, the target Cmin range was 3.6-8.2 μg/mL. The following formula to achieve a target Cmin in patients with different degrees of renal function was proposed based on these results: initial daily dose (mg/day)=CL × AUC₂₄=(0.0258 × CLCr + 2.03)×(18.2 × Cmin + 134.4). This recommended initial dosage and subsequent dosage adjustment for the target concentration range should avoid adverse events, thereby enabling effective linezolid-based therapies to be continued.
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
authors.forename: Akari
authors.initials: A
authors.lastname: Shigemi
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Takeshita
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Watanabe
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Yokoyama
authors.affiliation: Department of Clinical Pharmacotherapy, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
authors.forename: Kazuro
authors.initials: K
authors.lastname: Ikawa
authors.affiliation: Department of Clinical Pharmacotherapy, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Morikawa
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. Electronic address: takeda@m.kufm.kagoshima-u.ac.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takeda
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D005260:Female; D006801:Humans; D000069349:Linezolid; D008297:Male; D008657:Metabolic Clearance Rate; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D015233:Models, Statistical; D023303:Oxazolidinones / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010949:Plasma / Q000737:chemistry; D013921:Thrombocytopenia / Q000139:chemically induced*
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D000069349:Linezolid
keywords: Linezolid; Population pharmacokinetics; Therapeutic drug monitoring; Thrombocytopenia