Population pharmacokinetics of ampicillin and sulbactam in patients with community-acquired pneumonia: evaluation of the impact of renal impairment

Abstract

Aims: The aims of this study were to develop a population pharmacokinetic (PK) model of ampicillin and sulbactam, to identify patient characteristics influencing the PK, and to explore the relationship between dose regimen and degree of renal impairment with exposure and time above minimum inhibitory concentration (MIC).

Methods: This analysis was performed on PK data for ampicillin and sulbactam and MIC data from a clinical trial in Japanese patients with community acquired pneumonia. Simulations were performed to investigate the effects of different dosing intervals on exposure and time above MIC in various degrees of renal impairment.

Results: The plasma concentrations from 47 patients were adequately described by a two compartment model with simultaneous fit of ampicillin and sulbactam PK data, where creatinine clearance on clearance and body weight on volume in the peripheral compartment were identified as covariates for both drugs. Creatinine clearance contributed to reducing inter-individual variability of clearance by 16%. Mean clearance (inter-individual variability) for ampicillin and sulbactam was estimated to be 10.7 l h(-1) (14.8%) and 10.4 l h(-1) (15.2%), respectively. The time above MIC for each pathogen was generally > 50% of the treatment period. Simulations for exposure and time above MIC supported currently recommended dose adjustments.

Conclusions: This study provided a PK model for ampicillin and sulbactam, the time above MICs for identified pathogens and associated simulation results. These findings provide useful information and augment evidence for the established dosage regimens in patients with various degrees of renal impairment.

Trial registration: ClinicalTrials.gov NCT01189487.

Keywords: Unasyn; ampicillin; pneumonia; population pharmacokinetics; sulbactam.

© 2013 The British Pharmacological Society.

Figures

Figure 1

(A) Normal and (B) semilog-scaled observed plasma ampicillin and sulbactam concentrations vs. time profile. The time represents time after the start of the most recent intravenous infusion of ampicillin /sulbactam 3 g four times daily

Figure 2

(A) Scatter plots of observed plasma concentrations (DV) vs. population predicted concentrations (PRED) and DV vs. individual predicted concentrations (IPRED) for the final model. Each dotted line represents the concordance line (Y = X). (B) Scatter plots of residuals normalized by the SD of the data (conditional weighted residuals [CWRES]) vs. PRED and CWRES vs. time after the last dose for the final model. Dotted lines represent CWRES = 0 or ± 5. Note: circles and triangles represent ampicillin and sulbactam, respectively. Each solid line indicates a non-parametric regression with robust local linear fit

Figure 3

Visual predictive check plots representing concentration for ampicillin (left panel) and sulbactam (right panel) (μg ml−1) vs. time after the most recent administration (h). Each panel shows observed 10, 50 and 90th percentile points (black lines) and model predicted 95% CIs for 10, 50 and 90th percentile points (blue and red areas)

Figure 4

Box plots of simulated AUC for ampicillin (upper panels) and sulbactam (lower panels) following multiple 30 min intravenous infusions of 3 g ampicillin/sulbactam for 3 days of treatment by different renal functions with different dosing intervals. The dotted line represents the highest observed AUC (empirical Bayesian estimate) following intravenous administrations of ampicillin/sulbactam 3 g four times daily in CAP patients. Note: dosing intervals with under bar (in x-axis) represent recommended dosing intervals. QD once daily dosing, BID twice daily dosing, TID three times daily dosing, QID four times daily dosing

Figure 5

Probability of fraction of time above MIC for treatment period as unbound plasma ampicillin concentration (f t>MIC%) ≥ 30, 40 and 50% following multiple 30 min intravenous infusions of 3 g ampicillin/sulbactam for 3 days of treatment. The lines represent the probability by each dosing interval (○ once daily, • twice daily, △ three times daily, ♦ four times daily). The solid lines represent recommended dosing intervals