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The Pharmacokinetics of Daptomycin in Moderately Obese, Morbidly Obese, and Matched Nonobese Subjects

From Cubist Pharmaceuticals, Inc, Lexington, Massachusetts. Dr Dvorchik's current affiliation is Barry Dvorchik and Associates, Inc, Tampa, Florida.

Daptomycin pharmacokinetics were studied in adult volunteers who were moderately obese (body mass index [BMI] = 25-39.9 kg/m²) or morbidly obese (BMI 40 kg/m²) and a matched (gender, age, renal function) nonobese (BMI between 18.5 and 24.9 kg/m²) control group. All subjects received a dose of 4 mg/kg total body weight (TBW) by intravenous infusion (30 minutes). Daptomycin plasma half-life, the fraction of the dose excreted unchanged in urine, and daptomycin absolute renal clearance (mL/h) were unchanged as a function of obesity. The absolute volume of distribution (V_z and V_ss) and plasma clearance (CL) for daptomycin were higher in obese subjects as compared to nonobese matched controls. The rate of change of V_z and CL with increasing BMI was greater when these pharmacokinetic parameters were expressed in absolute terms compared to when they were normalized for TBW or ideal body weight. This suggests that increases in body mass associated with obesity are proportionality higher than the corresponding increases in V_d and CL. Exposure to daptomycin in obese subjects (C_max, AUC) was increased 25% and 30%, respectively, compared to nonobese matched controls, well within the range that was previously determined to be safe and well tolerated. Daptomycin may be dosed based on total body weight, and no adjustment in daptomycin dose or dose regimen should be required based solely on obesity.

Key Words: Daptomycin • obesity • pharmacokinetics • drug safety • drug distribution and elimination

Address for reprints: Megan Robertson, Cubist Pharmaceuticals, Inc, 65 Hayden Avenue, Lexington, MA 02421.

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