Initial Phase of Severe Sepsis and Septic Shock Clinical Trial
Official title:
Population Pharmacokinetics and Monte Carlo Dosing Simulations of Meropenem During the Early Phase of Severe Sepsis and Septic Shock in Critically Ill Patients in Intensive Care Units
This is a prospective, noncomparative study to assess the pharmacodynamics of meropenem
during early phase of severe sepsis and septic shock in critically ill patients in an
intensive care unit.
Clinical and laboratory data such as age,sex, body weight, electrolyte, vital signs, APACHE
II score, SOFA score, BUN, Cr and blood culture will be collected.
Twelve patients will be enrolled in this study. Meropenem pharmacokinetic will be carried
out during the first and second dose after 1g meropenem administration. Blood samples
(approximately 3 ml) will be obtained by direct venepuncture at the following time: 0, 0.25,
0.5, 1, 1.25, 1.5, 2, 2.5, 3, 4, 5, 8, 8.5, 9, 9.5, 10, 12, 14 and 16 h.
Meropenem assays will be performed by modified method of Ozkan et al. (Biomed. Chromatogr.,
2001).
The pharmacokinetics of meropenem will be modelled from concentration-time profile using
compartmental model. Monte Carlo simulation to assess PK/PD index as 40% and 100% T>MIC will
be conducted and the results will be reported as % PTA (Probability Target Attainment) and
%CFR (Cumulative Faction Response)
Introduction:
Severe sepsis/septic shock are one of the most important reasons for admission the
critically-ill patient to Intensive Care Units (ICU) and remaining a major causes of high
mortality. Evidently, the fluctuation in pathophysiology, particularly during early phase,
of this condition may result in PK alteration and lead to the inadequate antibiotic dosed of
standard treatment. Therefore, thearly phase treatment with an appropriate antimicrobial
doses that achieved pharmacodynamic target for antimicrobial therapy have been the crucial
factor for therapeutic.
Meropenem, a carbapenem antibiotic, is a β-lactam antimicrobial agent with a broad spectrum
of activity, coverage of gram-negative bacteria including highly resistant pathogens for
instance ESBL-producing or AmpC-mediated b-lactamase producing Enterobacteriaceae. This
agent, in common with other β-lactams, is characterized by time-dependent antimicrobial
activity, and the exposure time during which the free drug concentrations remains above the
minimum inhibitory concentration (T>MIC) is the pharmacokinetic/pharmacodynamic (PK/PD)
index that best correlates with efficacy. The majority of previous PK/PDs studies on
β-lactams in critically ill patients were mostly conducted in the steady-state period of
treatment in which during the early phase of severe sepsis/septic shock was still lacking.
Objectives:
To study the population PK of meropenem and assess the probability of target attainment
(PTA) of meropenem inthe initial phases of severe sepsis or septic shock patients in order
to be able to optimize dosing recommendations.
Clinical and laboratory data:
Age, sex, body weight, electrolite, vitalsigns, APACHAE II score, BUN, Cr, blood culture
Drug preparation and administration:
The dosage of meropenem was 1-h infusion of 1g diluted in 100 mL of normal saline solution
via infusion pump at a constant flow rate every 8 h (q8h) for 16 hours.
Study design:
Prospective non-comparative studyof 9 patients during the initial 24 h of severe sepsis or
septic shock. Each subject received a 1-h infusion of 1 g q8h of meropenem for 16 hrs. Monte
Carlo simulation were attempted to analyze the pharmacokinetics of experimental data.
Sample collection:
Meropenem PK studies were carried out during the administration of the first and second dose
of meropenem (0-16 h after the start of administration of meropenem). Blood samples (ca. 3
mL) were obtained by direct venipuncture at the following times: shortly before (time 0) and
then at 0.25, 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 4, 5, 8, 8.5, 9, 9.5, 10, 12, 14 and 16 h after
the start of administration of meropenem. All blood samples were added to a heparinized
tube, were immediately stored on ice and were centrifuged at 2000 × g at 4◦C for 10 min
within 5 min. All plasma samples were stored at -80◦C until analysis within 1 week.
Moropenem assay:
The meropenem assays by method of Ozkan et al. (Biomed Chromatogr, 2001) will be performed
at Department of Medicine, Faculty of Medicine.
Duration of study:
Patients will receive a 1-h infusion of 1 g q8h of meropenem for 16 hrs.
Pharmacokinetic and pharmacodynamic analysis:
Concentration of meropenem in plasma will be simulated in Monte Carlo technique to get PK/PD
index (40% and 80% PTA)
Sample size: Nine patients with severe sepsis and septic shock.
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Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label