title: Comparative pharmacokinetics and pharmacodynamics of doripenem and meropenem in obese patients.
abstract: BACKGROUND
  Antimicrobial pharmacokinetic and pharmacodynamic data are limited in obesity.
  
  
  OBJECTIVE
  To evaluate the steady-state pharmacokinetics and pharmacodynamics of doripenem and meropenem in obese patients hospitalized on a general ward.
  
  
  METHODS
  Patients with a body mass index (BMI) ≥40 kg/m² or total body weight (TBW) ≥100 pounds over their ideal body weight randomly received doripenem 500 mg (1-hour infusion) or meropenem 1 g (0.5-hour infusion) every 8 hours. Differences in pharmacokinetic parameters were determined by unpaired t test. Monte Carlo simulations were performed for 500 mg and 1 g every 8 hours, infused over 1 and 4 hours for doripenem and 0.5 and 3 hours for meropenem. Probability of target attainment (PTA) was calculated using a pharmacodynamic target of 40% fT > MIC (free drug concentrations above the minimum inhibitory concentration [MIC]), and cumulative fraction of response (CFR) was calculated using MIC data for 8 Gram-negative pathogens.
  
  
  RESULTS
  Twenty patients were studied. Volume of distribution at steady state, corrected for TBW, was significantly larger (0.18 ± 0.04 vs 0.13 ± 0.05 L/kg, P = .048) and systemic clearance was significantly faster for doripenem (11.7 ± 4.1 vs 8.1 ± 2.6 L/h, P = .03). PTA was >90% for all regimens at MICs ≤2 µg/mL. CFR was >90% for all regimens against 6 enteric Gram-negative pathogens and for 3 of 4 regimens for each drug against Pseudomonas aeruginosa.
  
  
  CONCLUSIONS
  Doripenem and meropenem pharmacokinetics differ in obesity. However, currently approved dosing regimens provide adequate pharmacodynamic exposures for susceptible bacteria in obese patients.
authors.affiliation: Purdue University College of Pharmacy, Indianapolis and West Lafayette, IN, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Kays
authors.forename: Megan R
authors.initials: MR
authors.lastname: Fleming
authors.forename: S Christian
authors.initials: SC
authors.lastname: Cheatham
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Chung
authors.forename: Joetta M
authors.initials: JM
authors.lastname: Juenke
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D015780:Carbapenems / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077726:Doripenem; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D009765:Obesity / Q000378:metabolism*; D013845:Thienamycins / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D013845:Thienamycins; D000077726:Doripenem; D000077731:Meropenem
keywords: doripenem; meropenem; obesity; pharmacodynamics; pharmacokinetics