Study Question: Are the pharmacokinetics (PK) and pharmacodynamics (PD) of meropenem and doripenem altered in hospitalized, non-critically ill, obese patients? If so, are dose adjustments warranted?
Study Description: This was a prospective PK/PD evaluation of meropenem and doripenem in adult, obese [body mass index (BMI) ≥ 40 kg/m2 or total body weight (TBW) ≥ 100 pounds over ideal body weight (IBW)] hospitalized general medical ward patients. Only patients with normal renal function were included. Patients were randomized to receive either doripenem 500 mg IV every 8 hours (infused over 1 hour) or meropenem 1 g IV every 8 hours (infused over 0.5 hour). After steady-state concentrations were reached, a series of blood samples were collected in order to fit the data to a concentration-time profile.
PK parameters were estimated using compartmental methods and PK models were fit to concentration-time data with the best PK model fit being a 2-compartment model with first-order elimination from the central compartment. PD exposures were modeled using the PK parameters derived in this study and using Monte Carlo stimulations for 5,000 patients. 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 PD target of 40% fT>MIC and cumulative fraction of response (CFR) was calculated using MIC data for 8 Gram-negative pathogens from the Tracking Resistance in the United States Today (TRUST) surveillance program. Dosing regimens were considered optimal if the PTA and CFR were ≥ 90%.
Results: Twenty patients were included (10 patients in each group) and baseline demographics were comparable between the groups. Steady-state parameters of Cmax (21 ± 7.4 vs. 62.6 ± 16.3 mg/L, p < 0.001), Cmin (1.6 ± 1.5 vs. 4.9 ± 4.2 mg/L, p = 0.03), and AUC0-τ (47.6 ± 20.8 vs. 138.3 ± 48.1 mg*h/L, p < 0.001) were found to be significantly lower in the doripenem group compared to the meropenem group. When corrected for TBW, volume of distribution at steady-state (Vss) was significantly larger (0.178 ± 0.041 vs. 0.133 ± 0.053 L/kg TBW, p = 0.048) and systemic clearance (Cls) was faster (0.071 ± 0.034 vs. 0.043 ± 0.017 L/h/kg TBW, p = 0.03) in the doripenem group. There was a significant relationship between volumes of distribution (V2, Vss) and body size (TBW, BMI) for the doripenem group. Relationships between different volumes and body sizes, as well as Cls and creatinine clearance, were not significant in the meropenem group.
A PTA of ≥ 90% was achieved in all dosing regimens at MICs ≤ 2 mcg/mL. Only doripenem 500 mg IV every 8 hours (1 hour infusion) and meropenem IV every 8 hours (0.5 hour infusion) did not achieve a PTA of > 90% at a MIC of 4 mcg/mL. Prolonged infusions for both drugs (1 g every 8 hours) achieved a PTA > 90% at an MIC of 8 mcg/mL. All regimens achieved a CFR > 98% for Enterobacteriacae; only doripenem 500 mg IV every 8 hour (1 hour infusion) and meropenem 500 mg IV every 8 hour (0.5 hour infusion) achieved a CFR < 90% for P. aeruginosa. No dosing regimen achieved a CFR > 73% for Acinetobacter species.
Conclusion(s): Doripenem and meropenem PK parameters are altered in obese patients, however, currently approved dosing regimens provide adequate exposures for susceptible pathogens in these patients.
Perspective: The prevalence of obesity and morbid obesity continues to grow in the United States and worldwide, increasing the likelihood that clinicians will encounter these patients in practice. The need to understand, recommend, and employ appropriate dosing regimens in this population is growing. This study demonstrated that although PK parameters may be altered in obese patients, dose modification may not be necessary. As a reminder, this study did not evaluate was antibiotic penetration at the site of infection or evaluate clinical outcomes. Furthermore, clinicians may not be able to extrapolate the findings beyond the obese patient populations.