Tedizolid Population Pharmacokinetics, Exposure Response, and Target Attainment

Abstract

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...

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

“…Therapeutic efficacies of linezolid and tedizolid are driven by their respective ratios of the area under the concentration-time curve over the dosing interval () at steady state for free drug to the MIC (fAUC 0 -/MIC ) (49,50). Because the PK properties of tedizolid allow for once-daily dosing while maintaining an fAUC/MIC sufficient for activity (30,43), the therapeutically effective daily dose of tedizolid can be reduced to 200 mg, which is 6 times lower than that of linezolid (1,200 mg). The resulting differences in drug exposures are magnified further by the greater protein binding and distribution of tedizolid in the body (30), resulting in free exposures that are 19 times higher for linezolid than for tedizolid based on the fAUC, 33 times higher based on the C max , and 49 times higher based on the C min , based on previously published data for both agents (25,41).…”

“…An additional factor that may contribute to fewer mitochondrial effects with tedizolid than with linezolid might be the substantial drug accumulation (and increased plasma concentrations) with repeated administration of linezolid (25,51,52). In contrast, most tedizolid-treated patients stay within the desired exposure window, allowing mitochondrial recovery because of narrow PK variability and a lack of significant accumulation (43,52). It is speculated that accumulation of linezolid is caused by impairment of hepatic mitochondria, leading to autoinhibition of its metabolism (53).…”

“…Human free plasma concentration-time data for tedizolid and linezolid in relation to the MPS IC 50 of each drug were evaluated to compare the potential for mitochondrial recovery between tedizolid and linezolid given at therapeutic doses; pharmacokinetic (PK) data were derived from two sources: (i) extensively sampled data from healthy subjects (25,41) and (ii) Monte Carlo simulations. Simulations were conducted based on previously presented population PK models for tedizolid and linezolid (42,43). Two sets of 2,500 virtual patients were generated by resampling the characteristics of patients in the combined population from phase 3 studies comparing tedizolid and linezolid against acute bacterial skin and skin structure infections.…”

“…Simulated drug concentrations at 10-min increments over the dosing interval were obtained based on the respective final population PK models, including covariate effects. Ideal body weight and total bilirubin were significant covariates in the tedizolid population PK model, and weight and age were significant covariates in the linezolid population PK model (42,43). Thus, these covariates were randomly resampled from the vectors of patient characteristics from the combined population of phase 3 patients in order to maintain the covariance structure inherent between covariates.…”

Effects of Tedizolid Phosphate on Survival Outcomes and Suppression of Production of Staphylococcal Toxins in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia

“…In uninfected rabbits, the tedizolid area under the concentration-time curve from 0 to 24 h (AUC 0 -24; mean Ϯ standard deviation [SD]) was 5.7 Ϯ 0.9 g · h/ml for a single intravenous dose of 2.5 mg/kg of body weight tedizolid phosphate, 9.9 Ϯ 1.5 g · h/ml for 5 mg/kg tedizolid phosphate, and 14.9 Ϯ 1.6 g · h/ml for 6 mg/kg tedizolid phosphate (Table 1). Because the intravenous administration of 6 mg/kg tedizolid phosphate yielded AUC 0 -24 values similar to those found in humans (14), we selected this dosing regimen for use in the rabbits.…”