Comparative Pharmacokinetics and Pharmacodynamics of Doripenem and Meropenem in Obese Patients

Purpose: To compare the pharmacokinetics and pharmacodynamics of doripenem and meropenem in obese patients.

Methods: Obese patients (BMI > 40 kg/m² or > 100 pounds over IBW) hospitalized on a general ward with CLcr ≥ 50 ml/min were randomized to receive doripenem 0.5 g q8h (1-h infusion) or meropenem 1 g q8h (0.5-h infusion). Serial blood samples were collected at steady-state, and drug concentrations were determined by ultraperformance liquid chromatography with tandem mass spectrometry detection. Pharmacokinetic parameters were estimated, 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: Twenty patients were studied. Mean ± SD BMI was 65 ± 28 kg/m² and 65 ± 17 kg/m² for doripenem and meropenem, respectively. Pharmacokinetic data are shown below. PTA was > 90% for MICs ≤ 2 mg/ml and ≤ 4 mg/ml for doripenem and meropenem, respectively. For both drugs, CFR was ≥ 90% for the 6 enteric gram-negative pathogens and P. aeruginosa, but only 66-71% for Acinetobacter species.

	Doripenem	Meropenem	p-value
Cmax (μg/ml)	21.0 ± 7.4	62.6 ± 16.3	< 0.0001
Cmin (μg/ml)	1.6 ± 1.5	4.9 ± 4.2	0.033
t1/2β (h)	2.7 ± 0.9	2.8 ± 1.4	NS
Vc (L)	15.7 ± 6.7	13.1 ± 5.5	NS
Vss (L)	32.2 ± 12.2	25.1 ± 9.1	NS
CLs (L/h)	11.7 ± 4.1	8.1 ± 2.6	0.03

Conclusions: For obese patients hospitalized on a general ward, doripenem 0.5 g q8h and meropenem 1 g q8h provide adequate pharmacodynamic exposures for enteric gram-negative pathogens and P. aeruginosa. Based on these data, dose escalation of these carbapenems based solely on obesity is unnecessary.