Single‐ and Multiple‐Dose Pharmacokinetics and Absolute Bioavailability of Tedizolid

Tedizolid is a novel oxazolidinone antimicrobial administered in its prodrug form, tedizolid phosphate, as a fixed once-daily dose. The pharmacokinetics of tedizolid has been studied in a relatively small proportion of morbidly obese (body mass index [BMI] of >40 kg/m 2 ) adults through population analyses with sparse sampling. The current study compared the intensively sampled plasma pharmacokinetics of tedizolid phosphate and tedizolid in 9 morbidly obese and 9 age-, sex-, and ideal body weight-matched nonobese (BMI, 18.5 to 29.9 kg/m 2 ) healthy adult (18 to 50 years of age) volunteers after administration of a single intravenous dose of tedizolid phosphate. The median (range) weights were 72.6 kg (58.9 to 89.5 kg) and 117 kg (102 to 176 kg) for the mostly female (77.8%) nonobese and morbidly obese adults, respectively. Tedizolid phosphate concentrations were below the limit of quantitation in a majority of subjects after the 2-h time point. The tedizolid median (range) maximum concentration of drug in plasma (C max ) and area under the concentration-time curve from 0 h to infinity (AUC 0 -ؕ ) were 2.38 (1.28 to 3.99) mg/liter and 26.3 (18.4 to 43.2) h · mg/liter, respectively, for morbidly obese subjects, and these were nonsignificantly different (P > 0.214) from the values for nonobese subjects. Similarly, the volumes of distribution (V z ) (P ‫؍‬ 0.110) and clearance (CL) values (P ‫؍‬ 0.214) were comparable between groups. Nearly identical (P ‫؍‬ 0.953) median tedizolid half-lives of approximately 12 h were observed for both groups. Tedizolid V z and CL scaled with body weight, but not proportionately. The small and nonsignificant differences in tedizolid AUC 0 -ؕ values between morbidly obese and nonobese subjects suggest that dose modification is not necessary for morbidly obese adults. (This study has been registered at ClinicalTrials.gov under number NCT02342418.) M ore than one-third of the U.S. adult population is classified as obese, based on having a body mass index (BMI) of Ն30 kg/m 2 (1). Acute bacterial skin and skin structure infections (ABSSSI) are common in obese patients, who are predisposed to developing type 2 diabetes (2). Tedizolid is a novel oncedaily oxazolidinone that was recently approved for the treatment of ABSSSI at 200 mg daily for 6 days. Tedizolid is a more potent oxazolidinone than linezolid, and it does not interact with selective serotonin reuptake inhibitors (SSRIs). This pharmacological difference is significant because the use of antidepressants is higher among obese adults than among nonobese adults in the United States (3, 4). As a consequence, tedizolid may be selected over linezolid for the treatment of ABSSSI in obese patients, who are potentially managed with SSRIs. To date, population pharmacokinetic (POP-PK) analyses have demonstrated that the concentration-time profiles of tedizolid are similar for subjects with class II obesity (BMI of Ն35 kg/m 2 ) and nonobese adults (BMI of Ͻ30 kg/m 2 ), suggesting that no dose modification for body size is necessary (5). In ...

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confidence: 53%

Pharmacokinetics of Tedizolid in Morbidly Obese and Covariate-Matched Nonobese Adults

Pai

2016

“…For instance, estimates of clearance and total volumes of distribution were similar to the corresponding values derived using noncompartmental analysis from phase 1 studies of tedizolid in healthy adult subjects. In those studies, tedizolid clearance was reported as 6.37 (Ϯ1.19) liter/h and 5.87 (Ϯ1.41) liter/h after single and multiple intravenous doses, respectively, and mean volume of distribution at steady state (V ss ) values ranged from approximately 67 to 80 liters (5,16). The model-estimated absolute bioavailability was also similar to the previously reported absolute bioavailability of 91% (17) and indicates that oral bioavailability is high.…”

Section: Discussionmentioning

confidence: 99%

“…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-daily administration (5). Tedizolid distributes freely into tissue, and both tedizolid phosphate and tedizolid are moderately protein bound (ϳ80%) in human plasma.…”

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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...

“…Only one strain, COL, was tested in this study. The treatment length was relatively brief (only 4 days), and a longer treatment may have produced more favorable results as with time the drug might accumulate in target tissues (19), increasing drug exposure. Whether there is a role for tedizolid phosphate in treatment of bacteremia from extracardiac sources also was not addressed in these experiments.…”

Section: Discussionmentioning

confidence: 99%

Comparative Efficacies of Tedizolid Phosphate, Vancomycin, and Daptomycin in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Endocarditis

Chan

Basuino

Dip

et al. 2015

Staphylococcus aureus is a common cause of skin and soft tissue infections and invasive disease, such as bacteremia and endocarditis. Tedizolid, the microbiologically active moiety of the prodrug tedizolid phosphate (TZD), is a novel oxazolidinone approved for treatment of acute bacterial skin and skin structure infections caused by Gram-positive bacteria, including strains of methicillin-resistant S. aureus (MRSA). Tedizolid phosphate is rapidly cleaved in the bloodstream to yield the active component, tedizolid. It is approximately 4 times more active by weight than linezolid against S. aureus in vitro (1) and 16 times more active against cfr plasmid carrying linezolid-resistant staphylococci in vitro (2). Moreover, unlike the bacteriostatic activity of linezolid, tedizolid has been shown to have some bactericidal activity in a neutropenic mouse thigh model (3, 4). To assess further its potency and bactericidal activity in vivo, tedizolid was compared to vancomycin and daptomycin in a rabbit model of aortic valve endocarditis (AVE) caused by the MRSA strain COL. MATERIALS AND METHODSBacterial strains. S. aureus strain COL is a homogeneous, methicillinresistant strain. COL inoculum was prepared by diluting a frozen stock in 0.9% injectable sodium chloride. The frozen stock was prepared from an overnight culture grown in tryptic soy broth. Cells were washed and resuspended in phosphate-buffered saline with 10% glycerol and stored at Ϫ80°C.Susceptibility studies. Susceptibility studies were performed by broth dilution to determine the MICs using standard CLSI methods (5). Briefly, the bacteria and drugs were diluted in cation-adjusted Mueller-Hinton broth (CAMHB) and incubated at 37°C overnight. Ca 2ϩ supplementation was provided for daptomycin testing (6). The MIC was determined as the lowest concentration of drug that inhibited growth. Tedizolid and daptomycin standard powder for in vitro testing were provided by the manufacturers, and vancomycin was purchased from Sigma-Aldrich.Time-kill studies. Time-kill studies were conducted in duplicate at 37°C in 10 ml of CAMHB containing vancomycin at 5 g/ml (5ϫ MIC), daptomycin at 5 g/ml (5ϫ MIC), or tedizolid at 2 g/ml (16ϫ MIC) at a starting inoculum of 10 6 CFU/ml. Rabbit model of endocarditis. New Zealand White rabbits (2.5 to 3 kg) were used. Endocarditis was established by standard methods (7). Briefly, a cutdown was made over the right carotid artery. A polyethylene catheter was introduced via carotid arteriotomy, positioned into the left ventricle, and sutured in place. Forty-eight hours later, a 1-ml suspension of 10 7 to 10 8 CFU of S. aureus in 0.9% NaCl was injected intravenously (i.v.). On postinoculation day 1, approximately 16 to 18 h after infection, untreated control rabbits were sacrificed to determine pretreatment bacterial counts. The hearts, spleens, and kidneys were harvested. Aortic valves and endocardial vegetations and approximately 0.2-g samples of spleen and kidney were placed in 1.0 ml of 0.9% NaCl and homogenized with a tissue grinder. Ten-...