ABSTRACT
BACKGROUND: The pharmacokinetics (PK) of antibiotics change during sepsis and continuous renal replacement therapies in critically ill patients. Limited evidence exists on the use of the oXiris® high-adsorbent membrane. OBJECTIVES: To develop a PK/pharmacodynamic (PD) model for meropenem in critically ill sepsis patients undergoing continuous venovenous haemodiafiltration (CVVHDF) with the oXiris® membrane, and to design an optimal dosing regimen assessed according to the PTA. METHODS: A prospective, open-label, observational PK trial was performed (EUDRACT 2011-005902-30). We conducted PK studies (plasma and ultrafiltrate) for at least 24 h after concomitant administration of CVVHDF and meropenem 1 g q8h. We constructed a PK model using the non-linear mixed-effects approach (NONMEM 7.3). We evaluated the suitability of different dosage regimens using Monte Carlo simulations and calculated the PTA as the percentage of subjects achieving a given percentage of time above the MIC (fT>MIC). RESULTS: The PK of meropenem was best captured by a two-open-compartment model with zero-order input kinetics and first-order elimination. Extracorporeal CL was 7.78 L/h [relative standard error (RSE) 16.45 L/h] and central compartment V (Vc) was 24.9 L (RSE 13.73 L). Simulations showed that, for susceptible Pseudomonas aeruginosa isolates (EUCAST MIC ≤2 mg/L) and attainment of 100%fT>MIC, 500 mg q8h given as extended (EI) or continuous infusion (CI) would be sufficient. For a target of 100%fT>4×MIC, CI of 3000 mg q24h or 2000 mg q8h administered as EI or CI would be required. CONCLUSIONS: We have constructed a PK model of meropenem in sepsis patients undergoing CVVHDF using the oXiris® membrane. This tool will support physicians when calculating the optimal initial dose.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacokinetics , Meropenem/administration & dosage , Meropenem/pharmacokinetics , Adult , Aged , Aged, 80 and over , Continuous Renal Replacement Therapy/methods , Critical Illness , Female , Humans , Male , Microbial Sensitivity Tests/methods , Middle Aged , Monte Carlo Method , Prospective Studies , Pseudomonas aeruginosa/drug effects , Sepsis/drug therapyABSTRACT
BACKGROUND: Infliximab (IFX) trough concentrations (Cmin) have been linked to treatment efficacy in psoriatic patients. Inter-individual IFX Cmin variability and factors influencing IFX pharmacokinetics could explain differences in treatment response. OBJECTIVE: To evaluate the association between IFX Cmin and clinical outcomes in psoriatic patients. METHODS: Prospective study of 33 patients with moderate to severe psoriasis receiving IFX at Bellvitge University Hospital, between October 2013 and November 2016. IFX Cmin and antibodies toward infliximab (ATI) were measured. RESULTS: We collected 155 IFX Cmin and ATI values (mean age, 46 (14) years; 11 (33.3%) women). Mean IFX Cmin was 2.5 (2.4) mg/L and ATIs were detected in six patients, resulting in undetectable IFX Cmin. IFX Cmin was significantly associated with ATI and body mass index (BMI) (ß -2.51, 95% CI -3.56 to -1.4 and ß -0.05, 95% CI -0.09 to -0.01). PASI score and PASI 90/100 response were significantly associated with IFX Cmin (IRR 0.80, 95% CI 0.70 to 0.92; OR 1.79, 95% CI 1.18 to 2.71 and OR 1.79, 95% CI 1.14 to 2.81). CONCLUSION: IFX Cmin significantly influences PASI 90/100 response rates. IFX Cmin wa significantly associated with ATI and BMI. The observed inter-individual variability in IFX Cmin supports the need for IFX drug monitoring.