Population Pharmacokinetics of Linezolid in Patients Treated in a Compassionate-Use Program

e Prolonged treatment with the oxazolidinone linezolid is associated with myelosuppression, lactic acidosis, and neuropathies, toxicities likely caused by impairment of mitochondrial protein synthesis (MPS). To evaluate the potential of the novel oxazolidinone tedizolid to cause similar side effects, nonclinical and pharmacokinetic assessments were conducted. In isolated rat heart mitochondria, tedizolid inhibited MPS more potently than did linezolid (average [؎ standard error of the mean] 50% inhibitory concentration [IC 50 ] for MPS of 0.31 ؎ 0.02 M versus 6.4 ؎ 1.2 M). However, a rigorous 9-month rat study comparing placebo and high-dose tedizolid (resulting in steady-state area under the plasma concentration-time curve values about 8-fold greater than those with the standard therapeutic dose in humans) showed no evidence of neuropathy. Additional studies explored why prolonged, high-dose tedizolid did not cause these mitochondriopathic side effects despite potent MPS inhibition by tedizolid. Murine macrophage (J774) cell fractionation studies found no evidence of a stable association of tedizolid with eukaryotic mitochondria. Monte Carlo simulations based on population pharmacokinetic models showed that over the course of a dosing interval using standard therapeutic doses, free plasma concentrations fell below the respective MPS IC 50 in 84% of tedizolid-treated patients (for a median duration of 7.94 h) and 38% of linezolid-treated patients (for a median duration of 0 h). Therapeutic doses of tedizolid, but not linezolid, may therefore allow for mitochondrial recovery during antibacterial therapy. The overall results suggest that tedizolid has less potential to cause myelosuppression and neuropathy than that of linezolid during prolonged treatment courses. This, however, remains a hypothesis that must be confirmed in clinical studies.

Section: Discussionmentioning

confidence: 99%

Nonclinical and Pharmacokinetic Assessments To Evaluate the Potential of Tedizolid and Linezolid To Affect Mitochondrial Function

Flanagan

McKee

Das

et al. 2015

“…MIC data reflect actual observations from patients enrolled in phase 3 studies, while AUCs were model derived for the same patients. which exhibited nonlinear PK and greater interpatient PK variability, possibly because of increasing autoinhibition of metabolism over time (13,14). The absorption model for tedizolid indicates a zero-order release of orally administered drug in the gastrointestinal tract (D1 parameter), with drug subsequently becoming available for absorption via a first-order process (k a ); therefore, the overall rate of absorption over time is depicted by a sigmoidal shape.…”

Section: Discussionmentioning

confidence: 99%

Tedizolid Population Pharmacokinetics, Exposure Response, and Target Attainment

Flanagan

Passarell

Lü

et al. 2014

bTedizolid phosphate is a novel antibacterial prodrug that is rapidly and extensively converted to its active moiety, tedizolid. We developed a population pharmacokinetics (PK) model for tedizolid using pooled data from seven densely and sparsely sampled clinical trials evaluating oral and intravenous tedizolid. Model-derived exposure estimates were evaluated for relationships to select efficacy and safety outcomes. A two-compartment model with sigmoidal absorption, absolute bioavailability, and linear elimination described the PK data well. Variability was small (clearance, 31% coefficient of variation; volume, 13.4% coefficient of variation), and absolute bioavailability was high (86%). No clinically significant covariate effects on tedizolid PK were found. Based on phase 3 data evaluating 200-mg once-daily tedizolid for acute bacterial skin and skin structure infections (ABSSSI), no relationships were seen between various efficacy outcomes and estimated tedizolid exposure; the estimated exposure range (freedrug area under the concentration-time curve over 24 h at steady state [AUC ss(0 -24) ], 7 to 50 g · h/ml) in these patients was modest. Safety data modeling, using once-daily doses of up to 400 mg, showed a small increase in the probability of an adverse event with increasing model-estimated tedizolid exposure; no such relationship was observed when specifically evaluating the 200-mg dose. There were no trends in neutrophil or platelet counts with increasing tedizolid exposure. Target attainment simulations for 200-mg tedizolid indicated a 98.31% probability of attaining the target measure (AUC for the free, unbound fraction of a drug [fAUC]/MIC ‫؍‬ 3) against a Staphylococcus aureus strain for which the MIC was <0.5 g/ml. These findings support 200-mg tedizolid once daily as the optimum dose for treatment of ABSSSI.T edizolid phosphate is a novel oxazolidinone prodrug antibacterial that is rapidly and extensively converted in vivo by phosphatases to microbiologically active tedizolid. It is intended for oral and intravenous administration in the management of Grampositive infections (1-3), including those caused by methicillinresistant Staphylococcus aureus (MRSA) (4). In two recent phase 3 studies, tedizolid (200 mg once daily for 6 days) demonstrated noninferior efficacy to linezolid (600 mg twice daily for 10 days) in the treatment of acute bacterial skin and skin structure infections (ABSSSI), along with a more favorable hematologic and gastrointestinal tolerability profile than linezolid (1, 2).The pharmacokinetics (PK) of tedizolid, studied extensively using noncompartmental analysis, were similar after administration of two solid forms of the prodrug, tedizolid phosphate and tedizolid phosphate disodium (an alternative prodrug used in tedizolid's early clinical development). The absolute bioavailability of tedizolid is high (Ͼ80%), peak plasma concentrations are achieved within approximately 3 h of oral dosing, and steady-state plasma concentrations are reached within 3 days of initiating once-dail...

“…A series of 10,000 subject Monte Carlo simulations (MCS) were performed in order to provide clinical context to the simulated regimens that were studied in the HFIM using Systat (version 13; Systat Software, Richmond, VA). Simulations were based on the population model from a large, previously published population pharmacokinetic analyses of 318 adult patients, all of whom received 600 mg of linezolid every 12 h (20). A protein binding level of 31% was utilized to calculate the free-drug AUC from the total AUC.…”

Section: Methodsmentioning

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

Self Cite

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.