Influence of Continuous Venovenous Hemofiltration and Continuous Venovenous Hemodiafiltration on the Disposition of Doripenem

Abstract

‫؍‬ 5). Healthy volunteers were also assessed (n ‫؍‬ 12). Concentrations of doripenem and the primary metabolite doripenem-M-1 were measured in plasma and ultrafiltrate or ultrafiltrate/dialysate by a validated liquid chromatography-tandem mass spectrometry method. In dialysisdependent subjects, levels of systemic exposure to doripenem and doripenem-M-1 were approximately 3-and 5-fold greater, respectively, than those in healthy subjects: for doripenem, 98 g ⅐ h/ml for CVVH and 77 g ⅐ h/ml for CVVHDF versus 32 g ⅐ h/ml for healthy subjects, and for doripenem-M-1, 24 g ⅐ h/ml for CVVH and 22 g ⅐ h/ml for CVVHDF versus 4.7 g ⅐ h/ml for healthy subjects. The mean sieving coefficients and saturation coefficients were >0.67 for both doripenem and doripenem-M-1. During CVVH and CVVHDF, respectively, the percentages of administered doripenem dose removed were 38% and 29%, and clearances of doripenem were 22 and 25 ml/min. Both CVVH and CVVHDF efficiently removed doripenem and doripenem-M-1. Despite significant removal of drug by CVVH and CVVHDF, a single 1-hour, 500-mg doripenem infusion produced significantly higher plasma concentrations of doripenem, higher systemic exposure (area under the plasma concentration-time curve from time zero to 12 h after the start of infusion [AUC 0-12 ]), and longer half-life (t 1/2 ) in subjects receiving CVVH or CVVHDF than in healthy volunteers. The recovery of drug in ultrafiltrate and ultrafiltrate/dialysate and the enhanced rate of reduction of plasma concentrations indicate that CVVH and CVVHDF significantly augmented residual total body clearance of doripenem in subjects receiving CRRT. Doripenem dosage regimens for patients receiving CRRT thus need to be adjusted.

Doripenem Treatment during Continuous Renal Replacement Therapy

“…Furthermore, concentration drops below 4 mg/liter during steady state could be observed in 15.2% of the cases. (3,4). The sieving coefficients observed in our study differed dramatically from those reported by Cirillo et al A possible explanation for the difference between prefilter/ postfilter clearance and sieving coefficient-dependent clearance could be adsorption of doripenem to the filter membrane.…”

“…The initial dosing recommendation for renally competent patients was 500 mg every 8 h (q8h). Based on this regimen, a pharmacokinetic (PK) trial with otherwise healthy patients on continuous renal replacement therapy (cRRT) was performed by Cirillo et al in 2011, showing reduced elimination of doripenem for patients on continuous renal replacement therapy relative to renally competent patients (3). These data were supported by a publication by Roberts et al in September 2014 (4).…”

Pharmacokinetics and pharmacodynamics of anti-infective agents during continuous veno-venous hemofiltration in critically ill patients: Lessons learned from an ancillary study of the IVOIRE trial

“…[33] Cirillo et al showed that both CVVH and CVVHD efficiently removed doripenem with an SC of respectively 67% and 76%. [34] We demonstrated that, despite acceptable in vivo concentrations of ertapenem or doripenem after bolus or continuous infusion, a prolonged (4 h) bolus or continuous infusion may be beneficial to keep concentrations longer above MIC. From our study, it can be concluded that imipenem should be replaced by doripenem or meropenem during CRRT.…”

Doripenem Dosing Recommendations for Critically Ill Patients Receiving Continuous Renal Replacement Therapy

“…With the goal of developing a dosing regimen, we utilized data from Cirillo et al [14] and conducted Monte Carlo simulations to propose doripenem dosage recommendations for subjects undergoing CVVH and CVVHDF. The simulations were performed using a pharmacokinetic model that was built using doripenem concentration time data from hemodialysis-dependent Stage 5 chronic kidney disease subjects who received CVVH or CVVHDF.…”

“…This assumption for doripenem is permissible because the parent drug does not accumulate to a significant extent, since it has a 1- to 4-hour plasma elimination half-life for various subject populations including subjects with severe chronic kidney disease [5, 6, 14, 19]; (4) stationary (or time-independent) pharmacodynamics was assumed wherein time-dependent phenomena such as postantibiotic effect and resistance development were not incorporated in the modeling process; (5) no formal model was developed to describe dropouts and complete compliance was assumed during simulations. This is a fair assumption because doripenem is administered intravenously under the supervision of a healthcare professional in a clinical setting; (6) interindividual variability for several parameters (e.g., protein binding and residual kidney function) was not incorporated in the simulations because such detailed information is not available; (7) the reported protein binding of 8.5% for doripenem [19] was also assumed to apply to CVVH and CVVHDF subjects; (8) residual variability was not introduced into the calculations of simulated concentrations since it was found to be insignificant; (9) the pharmacokinetic/pharmacodynamic target is based on plasma drug exposure associated with bacteriostatic effect ( f T > MIC 35% target).…”