Higher linezolid exposure and higher frequency of thrombocytopenia in patients with renal dysfunction.
The major adverse event associated with linezolid treatment is reversible myelosuppression, mostly thrombocytopenia. Recent studies have reported that the incidence of linezolid-induced thrombocytopenia was higher in patients with renal failure than in patients with normal renal function, although the underlying mechanisms of this toxicity are still unknown. The present study thus aimed to investigate the relationship between renal function and linezolid exposure as well as the effects of drug exposure on thrombocytopenia. A statistically significant (P<0.01) strong correlation (r=0.933) was observed between linezolid clearance and creatinine clearance. A negative correlation (r=-0.567) was also shown between linezolid clearance and blood urea nitrogen, although the correlation was not statistically significant. In thrombocytopenic patients, the trough concentration was 14.4-35.6 mg/L and the area under the plasma linezolid concentration-time curve for 24h (AUC(24h)) was 513.1-994.6 mg h/L; in non-thrombocytopenic patients, drug exposure was relatively low (6.9 mg/L and 7.2mg/L for trough concentration and 294.3 mg h/L and 323.6 mg h/L for AUC(24h)). These results provide a pharmacokinetic explanation for the mechanism of the adverse event that renal dysfunction increased linezolid trough concentration and AUC and that higher drug exposure induced thrombocytopenia.
Matsumoto
Kazuaki
K
Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
Takeshita
Ayumi
A
Ikawa
Kazuro
K
Shigemi
Akari
A
Yaji
Keiko
K
Shimodozono
Yoshihiro
Y
Morikawa
Norifumi
N
Takeda
Yasuo
Y
Yamada
Katsushi
K
D000081:Acetamides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000368:Aged; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007564:Japan; D000069349:Linezolid; D008297:Male; D023303:Oxazolidinones / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D051437:Renal Insufficiency / Q000503:physiopathology*; D012307:Risk Factors; D013921:Thrombocytopenia / Q000139:chemically induced*
D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D003404:Creatinine; D000069349:Linezolid