Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit

Abstract

Doripenem has been recently introduced in Malaysia and is used for severe infections in the intensive care unit. However, limited data currently exist to guide optimal dosing in this scenario. We aimed to describe the population pharmacokinetics of doripenem in Malaysian critically ill patients with sepsis and use Monte Carlo dosing simulations to develop clinically relevant dosing guidelines for these patients. In this pharmacokinetic study, 12 critically ill adult patients with sepsis receiving 500 mg of doripenem every 8 h as a 1-hour infusion were enrolled. Serial blood samples were collected on 2 different days, and population pharmacokinetic analysis was performed using a nonlinear mixed-effects modeling approach. A two-compartment linear model with between-subject and between-occasion variability on clearance was adequate in describing the data. The typical volume of distribution and clearance of doripenem in this cohort were 0.47 liters/kg and 0.14 liters/kg/h, respectively. Doripenem clearance was significantly influenced by patients' creatinine clearance (CL(CR)), such that a 30-ml/min increase in the estimated CL(CR) would increase doripenem CL by 52%. Monte Carlo dosing simulations suggested that, for pathogens with a MIC of 8 mg/liter, a dose of 1,000 mg every 8 h as a 4-h infusion is optimal for patients with a CL(CR) of 30 to 100 ml/min, while a dose of 2,000 mg every 8 h as a 4-h infusion is best for patients manifesting a CL(CR) of >100 ml/min. Findings from this study suggest that, for doripenem usage in Malaysian critically ill patients, an alternative dosing approach may be meritorious, particularly when multidrug resistance pathogens are involved.

FIG 1

Goodness-of-fit plots associated with the final population pharmacokinetic model for doripenem. The solid black line represents the line of identity, and the dashed gray line represents the smooth fitting for observations. Clinical observations are represented by black solid circles.

FIG 2

Visual predictive check plot associated with the final population pharmacokinetic model for doripenem. The solid black circles represent the observed data, the solid gray line represents the 50th percentile of the observed data, the solid black line represents the 50th percentile of the simulated data, the dashed gray lines represent the 5th and 95th percentiles of the observed data, the dashed black lines represent the 5th and 95th percentiles of the simulated data, and the shaded areas represent the 95% confidence intervals of the 5th, 50th, and 95th percentiles of the simulated plasma concentrations.

FIG 3

The probability of target attainment for various simulated doripenem dosing regimens to achieve 40% fT_>MIC in patients with a creatinine clearance of 30 ml/min (top left), 50 ml/min (top right), 70 ml/min (middle left), 100 ml/min (middle right), and 150 ml/min (bottom). The dashed black lines denote optimal doripenem dosing, which was signified by achieving at least 90% probability of target attainment.