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38 A Population Pharmacokinetic Study of Isepamicin in ICU Patients

 

M. Tod*(1) , C. Padoin(1) , C. Minozzi(2) , J. Cougnard(2) , O. Petitjean(1)

Department de pharmacotoxicologie, Hopital Avicenne, Bobigny cedex(1)
and Schering-Plough, Levallois-Perret(2) , France

The pharmacokinetics (PK) of isepamicin, a new aminoglycoside, were studied in 85 intensive care unit (ICU) patients and compared to those in 10 healthy volunteers (HV). A parametric population pharmacokinetic method based on a non linear mixed effect model was used. Isepamicin was given 15 mg/Kg o.d. or 7.5 mg/kg b.i.d. intravenously in 0.5 h. The data were fitted to a bicompartmental open model. Compared to HV, the mean PK parameters were deeply modified in ICU patients: elimination clearance (Cl) was reduced by 41%, while volume of the central compartment (Vc), volume of distribution at steady-state, distribution clearance and elimination half-life (T1/2) were respectively 31%, 95%, 135% and c. 2.7 times higher. The interindividual variability in PK parameters was around 50% in ICU patients. Five covariates (weight BW, SAPS, temperature, serum creatinine and creatinine clearance ClCR) were tentatively correlated with PK parameters by multivariate linear regression analysis with stepwise addition/deletion. The variability in isepamicin Cl was explained at 57% by BW and ClCR,, that in VC at 24% by BW and SAPS, and that in T1/2 at 49% by CLCR and SAPS. Simulation of the concentration vs. time profile over 200 individuals showed that the mean peak (0.75hr) concentration was 12% lower in ICU patients than in HV, and the range in ICU patients was very large (14.2 - 69.7mg/liter). Therefore isepamicin monitoring is mandatory in ICU patients.



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