LINEARITY OF PHARMACOKINETICS AND MODEL ESTIMATION OF SUFENTANIL

Background: The pharmacokinetic profiles of sufentanil available in th e literature are conflicting because of methodologic differences. Leng th of sampling and assay sensitivity are key factors involved in accur ately estimating the volumes of distribution, clearances, and eliminat ion phase. The unit disposition function of increasing doses of sufent anil were investigated and the influence of dose administered on the l inearity of pharmacokinetics was assessed. Methods: The pharmacokineti cs of sufentanil were investigated in 23 patients, aged 14-68 yr, sche duled for surgery with postoperative ventilation. After induction of a nesthesia, sufentanil was administered as a short infusion (10-20 min) in doses ranging from 250 mu g to 1,500 mu g. Frequent arterial blood samples were gathered during and at the end of infusion, then at spec ific intervals up to 48 h after infusion. Plasma concentrations of suf entanil were measured by radioimmunoassay (limit of sensitivity 0.02 n g . ml(-1)). The data were analyzed with the standard two-stage, naive pooled-data and the mixed effect pharmacokinetic approaches. Results: The pharmacokinetics of sufentanil were adequately described by a lin ear three-compartmental mamillary model with the following parameters, expressed as log mean values with 95% confidence intervals: the centr al volume of distribution = 14.3 l (13.1-15.4 l), the rapidly equilibr ating volume = 63.1 l (61.9-64.3 l), the slowly equilibrating volume = 261.6 l (260.2-262.9 l), the steady-state distribution volume = 339 l (335-343 l), metabolic clearance = 0.92 l . min(-1) (0.84-1.05 l . mi n(-1)), rapid distribution clearance = 1.55 l . min(-1) (1.34-2.14 l . min(-1)), slow distribution clearance = 0.33 l . min(-1) (0.27-0.49 l . min(-1)), and elimination half-life = 769 min (690-1011 min). No re lation to age, weight, or lean body mass was found for any of the para meters. Conclusions: Sufentanil pharmacokinetics were linear within th e dose range studied. Drug detection up to 24 h after dosing was neces sary to define the terminal elimination phase. The metabolic clearance approached liver blood flow and a large volume of distribution was id entified, consistent with the long terminal elimination half-life. Sim ulations predicted that plasma sufentanil steady-state concentrations would rapidly decline after termination of an infusion despite the lon g half-lives.