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POPULATION PHARMACOKINETICS OF CEFTRIAXONE IN
INTENSIVE CARE UNIT (ICU) ADULT PATIENTS C Le
Guellec (1), N Simon (2), D.Garot (3), R. Respaud
(1), P Lanotte (4), H. Blasco (1), PF Dequin
(3). (1) Department of clinical pharmacology,
University hospital, Tours, France. (2)
Department of clinical pharmacology, Université
de la méditerranée, APHM, Marseilles, France. (3)
Intensive acre unit, University hospital, Tours,
France. (4) Laboratory of microbiology,
University hospital, Tours, France
Introduction

• Covariate analysis showed that V1 increased with
  more severe type of sepsis (V1 8.21 3.55 L,
  9.77 3.83 L and 11.5 4.16 L for sepsis,
  severe sepsis and septic shock, respectively) but
  its inclusion in the model was not significant.
• Ceftriaxone CL was independent of CLcr for
  values below 60 ml/min and then increased
  linearly with GFR

• Pharmacokinetics of drugs used in critically ill
  patients may be altered because of renal or
  hepatic dysfunction, variation of vascular
  permeability, abnormal fluid balance, altered
  protein metabolism and low albumin.
• Ceftriaxone is a third generation cephalosporin
  with a broad spectrum activity against gram-
  positive and gram-negative bacteria.
• As a time-dependant antibiotic, the
  pharmacokinetic-pharmacodynamic parameter
  determining its in vivo efficacy is the time that
  serum levels exceeds 4xMIC.
• Although commonly used, there are few data on
  its pharmacokinetics in critically ill patients.

Objectives

• To describe population pharmacokinetics of
  ceftriaxone in a large group of critically ill
  patients suffering from sepsis, severe sepsis or
  septic shock
• To investigate the influence of several clinical
  and biological covariates on pharmacokinetic
  parameters
• To simulate various dosing regimen to evaluate
  whether some of them could produce concentrations
  below the MIC of common ICU pathogens.

• The model did not supported BOV on any
  parameter.
• The other PK parameters were V2 (7.35 L
  rse10.2 CV65) and intercompartment clearance
  (5.28 h-1 fixed). Residual variability modelled
  as proportional was 24.
• The VPCs obtained with the final model are shown
  below

Patients and Methods

• Prospective population pharmacokinetic study in
  patients receiving ceftriaxone (1 or 2 g once a
  day).
• MIC of bacterial isolates to ceftriaxone was
  determined by the E-test method
• A pharmacokinetic (PK) profile was obtained on
  two occasions for each patient.
• First PK on the second day of ceftriaxone
  therapy
• Second PK after the resolution of sepsis.
• Population pharmacokinetic analysis was
  performed using NONMEM VI.
• Fourteen potential covariates were evaluated,
  including demographic, biological and clinical
  characteristics, and co-administered drugs.
• Between Occasion Variability (BOV) was analyzed
  from PK1 to PK2.
• Precision and stability of parameter estimates
  were evaluated by non-parametric bootstrap
  procedure.
• Simulations were made at various doses for
  hypothetical patients having different covariate
  values and concentrations were compared to MICs
  of common ICU pathogens.

• Simulations performed for 2 different
  ceftriaxone doses and 4 different renal functions
  indicated that most patients will achieve
  effective concentrations, even with a dose of 1 g.

CLcr 180 ml/mn
CLcr 30 ml/mn
Résults
Conclusion

• We included 54 patients 19 suffered from
  sepsis, 9 from severe sepsis and 26 from septic
  shock.
• Eleven patients were hemofiltrated or
  haemodyalized. For the others, creatinine
  clearance (CLcr) ranged 5.5 to 214 ml/min. Renal
  function improved from PK1 to PK2 with median
  (range) values of 63 (5.5 - 195) and 70 (25.7 -
  214) mL/min, respectively.
• A 2-compartment pharmacokinetic model was
  selected

We found a wide inter-patient but weak
intrapatient variability of ceftriaxone PK. The
only parameter that influenced ceftriaxone
pharmacokinetics was CLcr, but only when CLcr was
gt 60 ml/min, suggesting participation of
non-renal phenomenon. Simulations indicated that
the risk of being under 4 MIC for the entire
dosing interval is very low and exists only in
patient with high glomerular filtration rate
(CLcr gt 120 ml/min).