Dataset Information

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

ABSTRACT: 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 (Cmax) and area under the concentration-time curve from 0 h to infinity (AUC0-?) 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 (Vz) (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 Vz and CL scaled with body weight, but not proportionately. The small and nonsignificant differences in tedizolid AUC0-? 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.).

SUBMITTER: Pai MP

PROVIDER: S-EPMC4958168 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Pai Manjunath P MP

Antimicrobial agents and chemotherapy 20160722 8

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 weigh ...[more]

PMID: 27185808

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Project description:Background/aimIncreased body mass index (BMI) and neck circumference are the two independent predictors of difficult intubation. McGrath MAC X-Blade is a videolaryngoscope specifically designed for difficult intubations.Materials and methodsEighty patients with the American Society of Anesthesiologists (ASA) physical status I–III undergoing elective surgery requiring endotracheal intubation were enrolled in the study. Patients were divided into two groups, nonobese (BMI < 30) and morbidly obese (BMI > 35). All patients were intubated with the McGrath MAC X-Blade in both groups. View optimization and tube insertion maneuvers such as reinsertion of the device, slight removal of the device, cricoid pressure, handling force, 90° anticlockwise rotation of the tube, use of stylet, and head flexion maneuvers were recorded. Cormack–Lehane grades, insertion times, intubation, and total intubation times were recorded. The hemodynamic changes and postoperative minor complications were also recorded.ResultsBody mass index, neck circumference, Mallampati scores, and ASA physical status were statistically higher in the morbidly obese group (P < 0.001 and P < 0.05). Sternomental distances were shorter in the morbidly obese (P < 0.05). Cormack–Lehane grades were comparable among the groups. The morbidly obese patients required more reinsertion attempts and cricoid pressure maneuvers during intubation than the nonobese patients (P = 0.019 versus P = 0.012, respectively). Slight removal of the device, handling force, use of the stylet, 90° anticlockwise rotation of the tube, and head flexion maneuvers were also helpful in both groups. Although device insertion times were similar between the groups, intubation and total intubation times were longer in the morbidly obese group (P = 0.009 and P = 0.034, respectively). The groups were comparable in hemodynamic changes and postoperative minor complications.ConclusionThe McGrath MAC X-Blade videolaryngoscope could safely be used both in nonobese (BMI < 30) and morbidly obese (BMI > 35) patients with the aid of some key maneuvers and with a statistically significant but clinically negligible prolongation of the intubation time.

Project description:The objectives of this study were the identification in (morbidly) obese and nonobese patients of (i) the most appropriate body size descriptor for fosfomycin dose adjustments and (ii) adequacy of the currently employed dosing regimens. Plasma and target site (interstitial fluid of subcutaneous adipose tissue) concentrations after fosfomycin administration (8 g) to 30 surgery patients (15 obese/15 nonobese) were obtained from a prospective clinical trial. After characterization of plasma and microdialysis-derived target site pharmacokinetics via population analysis, short-term infusions of fosfomycin 3 to 4 times daily were simulated. The adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target attainment (PTA) analysis based on the unbound drug-related targets of an %fT>MIC (the fraction of time that unbound fosfomycin concentrations exceed the MIC during 24 h) of 70 and an fAUC0-24h/MIC (the area under the concentration-time curve from 0 to 24 h for the unbound fraction of fosfomycin relative to the MIC) of 40.8 to 83.3. Lean body weight, fat mass, and creatinine clearance calculated via adjusted body weight (ABW) (CLCRCG_ABW) of all patients (body mass index [BMI] = 20.1 to 52.0 kg/m2) explained a considerable proportion of between-patient pharmacokinetic variability (up to 31.0% relative reduction). The steady-state unbound target site/plasma concentration ratio was 26.3% lower in (morbidly) obese than nonobese patients. For infections with fosfomycin-susceptible pathogens (MIC ≤ 16 mg/L), intermittent "high-dosage" intravenous (i.v.) fosfomycin (8 g, three times daily) was sufficient to treat patients with a CLCRCG_ABW of <130 mL/min, irrespective of the pharmacokinetic/pharmacodynamic indices considered. For infections by Pseudomonas aeruginosa with a MIC of 32 mg/L, when the index fAUC0-24h/MIC is applied, fosfomycin might represent a promising treatment option in obese and nonobese patients, especially in combination therapy to complement β-lactams, in which carbapenem-resistant P. aeruginosa is critical. In conclusion, fosfomycin showed excellent target site penetration in obese and nonobese patients. Dosing should be guided by renal function rather than obesity status. (This study has been registered in the EU Clinical Trials Register under EudraCT no. 2012-004383-22.).

Dataset Information

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

Publications

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

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