Are standard doses of piperacillin in piperacillin/tazobactam regimens adequate for the management of febrile neutropenia? Answers from population pharmacokinetic modelling and Monte Carlo simulations [PublishAheadOfPrint]

Changes in the pharmacokinetics of piperacillin in febrile neutropenic patients have been reported to result in sub-optimal exposures. This study aimed to develop a population pharmacokinetic model for piperacillin and perform dosing simulation to describe optimal dosing regimens for haematological malignancy patients with febrile neutropenia. Concentration-time data were obtained from previous prospective observational pharmacokinetic and interventional therapeutic drug monitoring studies. Non-parametric population pharmacokinetic analysis and Monte Carlo dosing simulations were performed with Pmetrics® package for R. A two-compartment model with between-subject variability for clearance (CL), adequately described the data from thirty-seven patients (21 males, mean ±SD age 59 ± 12 years and weight 77 ± 16 kg). Parameter estimates were CL, 18.0 ± 4.8 L/h; central compartment V, 14.3 ± 7.3 L; rate constant Kcp, 1.40 ± 1.35 h^-1and Kpc, 4.99 ± 7.81 h^-1. High creatinine clearance (CL_CR) was associated with reduced probability of target attainment (PTA). Extended and continuous infusion regimens achieved a high PTA of > 90% for 50% fT_>MIC. Only continuous regimens achieved > 90% PTA for 100% fT_>MIC when CL_CR was high. The cumulative fraction of response (FTA) was sub-optimal (< 85%) for conventional regimens for both empiric and directed therapy considering 50% and 100% fT_>MIC. FTA was maximized with prolonged infusions. Overall, changes in piperacillin pharmacokinetics and the consequences on to therapeutic dosing requirements appear similar to those observed in intensive care patients. Guidelines should address the altered dosing needs of febrile neutropenic patients exhibiting high CL_CR or with known/presumed infections from high MIC bacteria.

http://ift.tt/2uJxWoO