Pharmacokinetics of paracetamol (Perfalgan®) following different infusion protocols in a porcine model
Introduction: Perfalgan® is a newly developed; direct inject able form of paracetamol. The recommended infusion rate for Perfalgan® is 1g over 15 minutes. This recommendation is based on the rationale that paracetamol acts centrally and to achieve an efficacious cerebrospinal fluid (CSF) level of p...
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Perfalgan® is a newly developed; direct inject able form of paracetamol. The recommended infusion rate for Perfalgan® is 1g over 15 minutes. This recommendation is based on the rationale that paracetamol acts centrally and to achieve an efficacious cerebrospinal fluid (CSF) level of paracetamol a high gradient between plasma and liquor is essential.
Aim of the trial:
Aim of the present investigation was to evaluate, whether similar efficacious CSF levels of Perfalgan® could be obtained after an infusion rate of 1g over 60 minutes.
Experiments were performed in 10 anaesthetized female German domestic pigs. The pigs were randomized either in the group with an infusion rate of 15 minutes (n=5) or 60 minutes (n=5). In the 15-minutes-group plasma and CSF samples were taken 15, 30, 60, 90 120, 150, 180, and 210 minutes after starting the infusion. In the 60-minutes-group plasma samples were taken 60 minutes after starting the infusion and every 30 minutes up to 210 minutes. CSF samples were obtained after 90, 120, 150, 180, and 210 minutes.
There were no differences between the groups regarding age (15-min-group: 11 - 13 weeks; 60-min-group: 11 - 14 weeks) and body weight (15-min-group: 38.8 – 41.7 kg; 60-min-group: 38.5 – 41.9 kg).
The elimination half-life (t ½ beta) of the drug was found to be longer in 60-minutes-group [(median±SD) 176± 127.62min] as compared to that in 15-min-group [120± 28.72 min]. The clearance (Cl) was lower in the 60-min-group [(median±SD) 94.9±45.73 ml/l)] as compared to that in the15-min-group [181±67 ml/l]. The values of maximum plasma concentration (C max) were (median±SD) 35.1± 17.48 in the 15-min-group and 37± 7.42 mg/l in the 60-min-group. The volumes of distribution at steady state (Vss) were (median+/-SD) 31.5±8.46 l in 15-min-group and 25.2±8.18 l in the 60-min-group.
Our results indicate that plasma levels are higher in the 60-minutes-group as compared to that in 15-minutes-group in the time interval between 60 and 180 minutes after starting the infusion. In the time interval between 90 and 210 minutes CSF levels were similar in both groups.
The intravenous infusion of 1g paracetamol over a period of 60 minutes instead of recommended duration of 15 minutes results in higher plasma and similar CSF concentrations. Pharmacokinetics suggests that, the analgesic effect of paracetamol for an infusion over 60 minutes is superior to the recommended infusion over 15 minutes. The infusion protocol for patients´ treatment should be scrutinized in randomized clinical trial|
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