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Purpose: To evaluate the pharmacokinetics and pharmacodynamics of doripenem in obese patients who are hospitalized in an intensive care unit.
Methods: Patients with a BMI > 40 kg/m2 or who were > 100 pounds over their ideal body weight and who were hospitalized in an intensive care unit were enrolled. All patients received doripenem 0.5 g IV q8h, infused over 1 h. Serial blood samples and urine were collected at steady-state, and doripenem concentrations were determined by ultraperformance liquid chromatography with tandem mass spectrometry detection. Pharmacokinetic parameters were estimated (best fit 2-compartment model), and 5,000-patient Monte Carlo simulations were performed to calculate the probability of target attainment (PTA) at specific MICs using a pharmacodynamic target of 40% fT>MIC. Cumulative fraction of response (CFR) was calculated using MIC data for 8 gram-negative pathogens from the TRUST surveillance program (TRUST 11-13).
Results: Ten patients were studied. Patient demographics were (mean ± SD): age 53 ± 10 years; weight 173 ± 37 kg; BMI 59.6 ± 16.8 kg/m2; measured CLcr 138 ± 42 ml/min. Mean ± SD Cmax, Cmin, terminal elimination rate, elimination half-life, Vc, Vss, CLs, and CLr were 15.4 ± 3.4 μg/ml, 1.5 ± 0.7 μg/ml, 0.24 ± 0.08 h-1, 3.2 ± 1.1 h, 24.5 ± 8.7 L (0.14 ± 0.04 L/kg), 44.6 ± 13.8 L (0.26 ± 0.06 L/kg), 13.0 ± 3.2 L/h, and 6.7 ± 3.1 L/h, respectively. PTA was ≥ 92% for MICs ≤ 2 mg/ml. CFR was ≥ 98% for the 6 enteric gram-negative pathogens, 88.1% for P. aeruginosa, and 64.3% for Acinetobacter species.
Conclusions: For obese patients hospitalized in an intensive care unit, doripenem 0.5 g IV q8h provides adequate pharmacodynamic exposures for bacterial pathogens with MICs ≤ 2 μg/ml. However, larger or alternative dosing regimens may be required for less susceptible pathogens.