Population Pharmacokinetic and Pharmacodynamic Analysis of Linezolid and a Hematologic Side Effect, Thrombocytopenia, in Japanese Patients

dLinezolid is a promising antimicrobial agent for the treatment of multidrug-resistant tuberculosis (MDR-TB), but its use is limited by toxicity. Therapeutic drug monitoring (TDM) may help to minimize toxicity while adequate drug exposure is maintained. Conventional plasma sampling and monitoring might be hindered in many parts of the world by logistical problems that may be solved by dried blood spot (DBS) sampling. The aim of this study was to develop and validate a novel method for TDM of linezolid in MDR-TB patients using DBS sampling. Plasma, venous DBS, and capillary DBS specimens were obtained simultaneously from eight patients receiving linezolid. A DBS sampling method was developed and clinically validated by comparing DBS with plasma results using Passing-Bablok regression and Bland-Altman analysis. This study showed that DBS analysis was reproducible and robust. Accuracy and between-and within-day precision values from three validations presented as bias and coefficient of variation (CV) were less than 17.2% for the lower limit of quantification and less than 7.8% for other levels. The method showed a high recovery of approximately 95% and a low matrix effect of less than 8.7%. DBS specimens were stable at 37°C for 2 months and at 50°C for 1 week. The ratio of the concentration of linezolid in DBS samples to that in plasma was 1.2 (95% confidence interval [CI], 1.12 to 1.27). Linezolid exposure calculated from concentrations DBS samples and plasma showed good agreement. In conclusion, DBS analysis of linezolid is a promising tool to optimize linezolid treatment in MDR-TB patients. An easy sampling procedure and high sample stability may facilitate TDM, even in underdeveloped countries with limited resources and where conventional plasma sampling is not feasible.

Section: Discussionmentioning

confidence: 99%

Dried Blood Spot Analysis for Therapeutic Drug Monitoring of Linezolid in Patients with Multidrug-Resistant Tuberculosis

Bolhuis

Koster

et al. 2012

“…By comparison, approximately 80% of the administered dose of linezolid is eliminated renally (including 30% as linezolid, 40% as the metabolite PNU-142586, and 10% as the metabolite PNU-142300) (25). Linezolid-associated thrombocytopenia rates are higher in patients with severe renal impairment than in subjects with normal renal function (26)(27)(28) and might be related to drug or metabolite accumulation, because renal insufficiency is also associated with significant increases in linezolid plasma metabolite levels (29)(30)(31). Some authors have suggested therapeutic trough monitoring during linezolid use to improve efficacy and safety outcomes in patients with renal insufficiency (32).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Tedizolid in Subjects with Renal or Hepatic Impairment

Flanagan

Minassian

Morris

et al. 2014

Two open-label, single-dose, parallel-group studies were conducted to characterize the pharmacokinetics of the novel antibacterial tedizolid and the safety of tedizolid phosphate, its prodrug, in renally or hepatically impaired subjects. Tedizolid pharmacokinetics in subjects with severe renal impairment without dialysis support was compared with that of matched control subjects with normal renal function. Effects of hemodialysis on tedizolid pharmacokinetics were determined in a separate cohort of subjects undergoing long-term hemodialysis. Effects of hepatic impairment on tedizolid pharmacokinetics were determined in subjects with moderate or severe hepatic impairment and compared with those of matched control subjects with normal hepatic function. Each participant received a single oral (hepatic impairment) or intravenous (renal impairment) dose of tedizolid phosphate at 200 mg; hemodialysis subjects received two doses (separated by 7 days), before and after dialysis, in a crossover fashion. The pharmacokinetics of tedizolid was similar in subjects with severe renal impairment and controls (ϳ8% lower area under the concentration-time curve [AUC], with a nearly identical peak concentration) and in subjects undergoing hemodialysis before and after tedizolid phosphate administration (ϳ9% lower AUC, with a 15% higher peak concentration); <10% of the dose was removed during 4 h of hemodialysis. Tedizolid pharmacokinetics was only minimally altered in subjects with moderate or severe hepatic impairment; the AUC was increased approximately 22% and 34%, respectively, compared with that of subjects in the control group. Tedizolid phosphate was generally well tolerated in all participants. These results suggest that tedizolid phosphate dose adjustments are not necessary in patients with any degree of renal or hepatic impairment. (This study has been registered at ClinicalTrials.gov under registration numbers NCT01452828 [renal study] and NCT01431833 [hepatic study].)

“…The Monte Carlo simulations based on the model by Sasaki et al (25) highlighted the time and concentration dependence of platelet-related toxicity of linezolid. All front-loaded regimens (except for the highest-dose regimen) resulted in slightly higher predicted toxicity than the traditional regimen of 600 mg q12h: fractional decreases in platelets for front-loaded regimens were up to a median of 28%, versus 22% for the traditional regimen.…”

Section: Discussionmentioning

confidence: 99%

Front-Loaded Linezolid Regimens Result in Increased Killing and Suppression of the Accessory Gene Regulator System of Staphylococcus aureus

Tsuji

Brown

Parasrampuria

et al. 2012

f Front loading is a strategy used to optimize the pharmacodynamic profile of an antibiotic through the administration of high doses early in therapy for a short duration. Our aims were to evaluate the impact of front loading of linezolid regimens on bacterial killing and suppression of resistance and on RNAIII, the effector molecule of the accessory gene regulator system (encoded by agr) in methicillin-resistant Staphylococcus aureus (MRSA). Time-killing experiments over 48 h were utilized for linezolid against four strains of MRSA: USA100, USA300, USA400, and ATCC 29213. A hollow-fiber infection model simulated traditional and front-loaded human therapeutic regimens of linezolid versus USA300 at 10 6 CFU/ml over 240 h. Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity, with reductions of >1 log 10 CFU/ml for all strains. Front-loaded regimens that were administered over 5 days, 1,200 mg every 12 h (q12h) (total, 10 doses) and 2,400 mg q12h (total, 10 doses) followed by 300 mg q12h thereafter, resulted in sustained bactericidal activity, with reductions of the area under the CFU curve of ؊6.15 and ؊6.03, respectively, reaching undetectable limits at the 10-day study endpoint. All regimens displayed a reduction in RNAIII relative expression at 24 h and 240 h compared with that of the growth control. Monte Carlo simulations predicted a <1.27؋ increase in the fractional decreases in platelets for all front-loaded regimens versus the 600 mg q12h regimen, except for the highest-dose front-loaded regimen. Front-loading strategies for linezolid are promising and may be of utility in severe MRSA infections, where early aggressive therapy is necessary.