title: Population pharmacokinetic and pharmacodynamic analysis of linezolid and a hematologic side effect, thrombocytopenia, in Japanese patients.
abstract: Linezolid is an antimicrobial agent to treat infections by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). While effective, linezolid treatment frequently is associated with hematological side effects, especially thrombocytopenia. However, little is known about the mechanism of this side effect and the exposure-response relationship. The present population pharmacokinetic/pharmacodynamic (PPK/PD) study was undertaken to elucidate the factors that determine linezolid levels, the relationship between exposure to linezolid and a decrease in platelet counts, and appropriate dosage adjustments based on exposure levels. In total, 50 patients (135 plasma samples) were used for the PPK analysis. The PPK analysis revealed that renal function and severe liver cirrhosis (Child Pugh grade C) significantly affect the pharmacokinetics of linezolid according to the equation clearance (liter/h)=2.85×(creatinine clearance/60.9)0.618×0.472CIR (CIR indicates cirrhosis status; 0 for noncirrhosis, 1 for cirrhosis patients). Using 603 platelet counts from 45 patients, a PPK/PD analysis with a semimechanistic pharmacodynamic model described the relationship between linezolid exposure and platelet counts quantitatively, and the newly constructed model was validated using external data (776 platelet counts from 60 patients). Simulation indicated considerable risks in patients with insufficient renal function (creatinine clearance, ≤30 ml/min) or severe liver cirrhosis. For these patients, a reduced dosage (600 mg/day) would be recommended for sufficient efficacy (area under the concentration-time curve over 24 h in the steady state divided by the MIC, >100) and safety.
authors.affiliation: Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sasaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takane
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Ogawa
authors.forename: Sayaka
authors.initials: S
authors.lastname: Isagawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirota
authors.forename: Shun
authors.initials: S
authors.lastname: Higuchi
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Horii
authors.forename: Kenji
authors.initials: K
authors.lastname: Otsubo
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ieiri
mesh_terms: D000081:Acetamides / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D044466:Asian People; D005260:Female; D006801:Humans; D000069349:Linezolid; D008297:Male; D008875:Middle Aged; D023303:Oxazolidinones / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013921:Thrombocytopenia / Q000139:chemically induced*
chemical_list: D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D000069349:Linezolid