Pharmacokinetics of remifentanil and its major metabolite, remifentanil acid, in ICU patients with renal impairment.

BACKGROUND: The pharmacokinetics of remifentanil, an opioid analgesic metabolized by non-specific esterases, and its principal metabolite, remifentanil acid (RA), which is excreted via the kidneys, were assessed as part of an open-label safety study in intensive care unit (ICU) patients with varying degrees of renal impairment.
METHODS: Forty adult ICU patients with normal/mildly impaired renal function (creatinine clearance [CL(cr)] 62.9 (sd) 14.5 ml min(-1); n=10) or moderate/severe renal impairment (CL(cr) 14.7 (15.7) ml min(-1); n=30) were included. Remifentanil was infused for up to 72 h, at a starting rate of 6-9 microg kg(-1) h(-1) titrated to achieve a target sedation level, with additional propofol (0.5 mg kg(-1) h(-1)) if required. Intensive arterial sampling was performed for up to 72 h after infusion. Pharmacokinetic parameters obtained by simultaneous modelling of remifentanil and RA data were statistically compared between the two groups.
RESULTS: Remifentanil pharmacokinetics were not significantly affected by renal status. RA clearance in the moderate/severe group was reduced to about 25% that of the normal/mild group (41 (29) vs 176 (49) ml kg(-1) h(-1), P<0.0001). Metabolic ratio, a predictor of the ratio of RA to remifentanil concentrations at steady state, was approximately eight-fold higher in the moderate/severe group relative to the normal/mild group (116 (110) vs 15 (4), P<0.0001). Maximum RA levels approached 700 ng ml(-1) in the moderate/severe group.
CONCLUSIONS: Although RA accumulates in patients with moderate/severe renal impairment, pharmacokinetic modelling predicts that RA concentrations during a 9 microg kg(-1) h(-1) remifentanil infusion for up to 15 days would not exceed those reported in the present study, for which no associated prolongation of mu-opioid effects was observed.