Population Pharmacokinetics and Pharmacodynamics of Doripenem in Obese, Hospitalized Patients.
BACKGROUND
Doripenem population pharmacokinetics and dosing recommendations are limited in obesity.


OBJECTIVE
To evaluate the population pharmacokinetics and pharmacodynamics of doripenem in obese patients.


METHODS
Hospitalized adults with a body mass index (BMI) ≥ 40 kg/m2or total body weight (TBW) ≥45.5 kg over their ideal body weight received doripenem 500 mg every 8 hours, infused over 1 hour. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed for 5 intermittent and prolonged infusion dosing regimens to calculate probability of target attainment (PTA) at 40% and 100% fT>MIC (free drug concentrations above the minimum inhibitory concentration).


RESULTS
A total of 20 patients were studied: 10 in an intensive care unit (ICU) and 10 in a non-ICU. A 2-compartment model with first-order elimination best described the serum concentration-time data. Doripenem clearance (CL) was significantly associated with creatinine CL (CRCL), volume of the central compartment with TBW and ICU residence, and volume of the peripheral compartment with TBW ( P < 0.05). Using 40% fT>MIC, PTA was >90% for all simulated dosing regimens at MICs ≤2 mg/L. Using 100% fT>MIC, prolonged infusions of 1 g every 6 hours and 2 g every 8 hours achieved >90% PTA at MICs ≤2 mg/L.


CONCLUSIONS
CRCL, ICU residence, and TBW are significantly associated with doripenem pharmacokinetics. Currently approved dosing regimens provide adequate pharmacodynamic exposures at 40% fT>MIC for susceptible bacteria in obese patients. However, prolonged infusions of larger doses are needed if a higher pharmacodynamic target is desired.
1 Kyung Hee University College of Pharmacy, Dongdaemun-gu, Seoul, South Korea.
Eun Kyoung
EK
Chung
2 Eskenazi Health, Indianapolis, IN, USA.
Megan R
MR
Fleming
3 Franciscan St Francis Health, Indianapolis, IN, USA.
S Christian
SC
Cheatham
4 Purdue University College of Pharmacy, Indianapolis and West Lafayette, IN, USA.
Michael B
MB
Kays
D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D015992:Body Mass Index; D001835:Body Weight; D015780:Carbapenems / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D000077726:Doripenem; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000077726:Doripenem
Monte Carlo simulations; doripenem; obesity; pharmacodynamics; pharmacokinetics