Pharmacokinetics of Tedizolid in Obese and Nonobese Subjects.

Obesity, defined as body mass index (BMI) 30 kg/m2, is a growing problem worldwide; the prevalence is 38% in the US adult population.1 Obesity is a risk factor for infection and is associated with antimicrobial treatment failure2 and worse clinical outcomes.3 Communityacquired pneumonia and skin and soft-tissue infections are themost common indications for prescribing outpatient antibiotics for obese patients.4 Obesity can affect the ability of antimicrobial agents to attain therapeutic levels.5,6 Changes in clearance and volume of distribution that may occur in obese patients can alter the dose– exposure relationship with some drugs, resulting in the need to adjust the dose in this patient population.7 With the emergence of antibiotic resistance, dosing decisions become increasingly important. Tedizolid phosphate, the prodrug of the novel oxazolidinone tedizolid, has been approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in a number of countries, among them the United States and countries in the European Union.8,9 Tedizolid phosphate is rapidly and extensively converted by endogenous phosphatases to its microbiologically active moiety, tedizolid, after administration.10,11 Tedizolid is generally at least 4-fold more potent in vitro than linezolid, the only other currently marketed oxazolidinone antibacterial, against staphylococci (including methicillin-resistant Staphylococcus aureus), streptococci, and enterococci (including vancomycinresistant strains).10,12,13 In 2 recent phase 3 trials in patients with ABSSSIs, tedizolid (200 mg once daily for 6 days) demonstrated noninferior efficacy to linezolid (600 mg twice daily for 10 days) and was generally well tolerated.14,15 The pharmacokinetics (PK) of tedizolid allow for once-daily administration, either orally or intravenously, at equivalent doses.11 Available data suggest that systemic exposure to linezolid is lower in obese than in nonobese patients, which suggests that body weight and/or BMI may be important factors.16–18 The reason for this difference remains undetermined, as does whether linezolid dose modification is warranted for obese patients. In studies of tedizolid, exposure in elderly adults, adolescents, and subjects with severe hepatic or renal impairment (including those requiring hemodialysis) was similar to that in control groups following administration of oral or intravenous tedizolid 200 mg.19,20 The PK in obese subjects were not explicitly studied during the development of tedizolid, but approximately 28% of subjects in phase 1 studies were obese. Thus, a retrospective comparison of the extensive PK data obtained in obese and nonobese subjects would provide useful knowledge of tedizolid PK in obese patients, which could assist in dosing; this is the basis for the current investigation.