Population Pharmacokinetic Analysis of Linezolid in Low Body Weight Patients with Renal Dysfunction

Abstract

Linezolid has antibacterial activity against aerobic Gram-positive cocci, including methicillin-resistant Staphylococcus aureus (MRSA). Adjustment of the dose of linezolid has been proposed to be unnecessary in patients with reduced renal function. However, platelet counts and hemoglobin levels were shown to be significantly lower in such patients than in patients with normal renal function. The population pharmacokinetic (PPK) of linezolid was investigated in MRSA infected patients with renal dysfunction. Linezolid concentrations in serum were measured by high-performance liquid chromatography. PPK analysis was performed in the nonlinear mixed effects model (NONMEM) computer program. In the final PPK model, total body weight (TBW), estimated glomerular filtration rate (eGFR), hemoglobin (HB), and alanine amino transferase (ALT) were influential covariates on total body clearance (CL), and the volume of distribution (Vd) was affected by TBW, which was expressed as CL (L/h) = 0.00327 × TBW × eGFR(0.428) × HB(0.502) × 0.283 (ALT ≥ 100 IU/L) and CL (L/h) = 0.00327 × TBW × eGFR(0.428) × HB(0.502) (ALT < 100 IU/L), Vd (L) = 1.310 × TBW. The PPK parameters of linezolid obtained here are useful for the optimal use of linezolid with similar patient population characteristics.

Analysis of thrombocytopenic effects and population pharmacokinetics of linezolid: a dosage strategy according to the trough concentration target and renal function in adult patients

“…The intra-individual variability for V was fixed as 0 because it was very small (Á < 0.0025). Regarding CL, CL Cr was identified as the only covariate that significantly explained interindividual variability, whereas variability due to other unknown factors still remained (CV CL = 30.5%; Table 2) and was similar to previously reported values (CV CL = 31.3% [31] and 35.2% [20]). All relative standard error (standard error/estimate, %) values via the covariance step in NONMEM modelling were <23%, and all parameter estimates were in the range of the 95% CI using the bootstrap method.…”

Predictors of Inadequate Linezolid Concentrations after Standard Dosing in Critically Ill Patients

“…In contrast to the presence of ARDS and lactate, the cofactors weight, creatinine clearance, and impairment of liver function were described previously (15,(18)(19)(20)(21)(22)(23)(24)(25) (Fig. 4).…”

“…Several predictors, such as glomerular filtration rate (14,(18)(19)(20)(21)(22), body weight (18,(21)(22)(23)(24)(25), parameters of liver function (15,18,20), renal replacement therapy (15), and comedication such as rifampin (a potent P-glycoprotein inducer) (7), have already been described. However, the effects of other possible covariates, such as the presence of acute respiratory distress syndrome (ARDS), peritonitis, and single nucleotide polymorphisms of the P glycoprotein, remain unclear.…”

Treatment of Mediastinitis due to Methicillin-resistant Staphylococcus aureus in a Renal Dysfunction Patient Undergoing Adjustments to the Linezolid Dose

“…Furthermore, the Cmin of linezolid was similar between the wound exudate and serum. Previous studies investigating the pharmacokinetics of linezolid in patients have shown that changes in the renal function significantly affect the pharmacokinetics of linezolid (7,17). The present patient's glomerular filtration rate increased from 5.7 to 11.5 mL/min/1.73 m 2 during the administration of linezolid, which may have induced the small variations observed in the Cmin of linezolid after the daily dose of linezolid was changed from 600 to 300 mg/day.…”

“…However, several studies have reported a correlation between thrombocytopenia and linezolid overexposure in patients with renal dysfunction (6)(7)(8)(9). Furthermore, the prolonged use of linezolid has been shown to induce adverse hematological events (10,11).…”