Janet R Wade(1) ,
Britt-Marie Emanuelsson(2) ,
Lars L Gustafsson(3) ,
Mats O Karlsson(1)
Division of Pharmacokinetics, Uppsala University, Sweden(1) ,
Astra Pain Control, Sodertalje, Sweden(2) ,
Department of Clinical Pharmacology, Karolinska Institute,
Huddinge Hospital, Sweden(3) .
Ropivacaine is a new amide-type local anaesthetic drug similar to
bupivacaine. A study has been carried to out to investigate if
ropivacaine exhibited nonlinear pharmacokinetics. Doses of 20, 40
and 80 mg were given as 30 minute infusions, in random order, to
9 volunteers and blood samples were collected for 8 hours; both
total and free concentrations were determined. The doses were
administered at one week intervals. The 
-1-acid
glycoprotein (AAG) concentrations were determined at each dosing
occasion.
Model independent analysis showed that the pharmacokinetics of ropivacaine were linear but a slight increase in the free fraction of Cmax after the 80 mg dose pointed to concentration dependent protein binding at higher concentrations.
Population analysis of the data found that a three compartment model with saturable protein binding to AAG was most appropriate. The model was fit to the data using NONMEM (Version IV). Free CL and free Vss were estimated to be 551 L/h (SE 5.0%) and 898 L (SE 8.2%) respectively. The number of binding sites was estimated to be 0.90 (SE 7.6%) and the dissociation constant was estimated to be 0.17 mg/L (SE 8.4%).
In conclusion, despite the very large amount of data per subject, a three compartment model with saturable protein binding to AAG could not be successfully fit to each individual. The population analysis was able to detect and characterise the saturable protein binding parameters, with a high degree of precision.