Pharmacokinetics and pharmacodynamics of the three isomers of mivacurium in health, in end-stage renal failure and in patients with impaired renal function

Abstract

We have studied the pharmacokinetics of cis-trans, trans-trans and cis-cis mivacurium in nine healthy patients (creatinine clearance 66-133 ml min-1), in seven patients with end-stage renal failure requiring dialysis (creatinine clearance 4-11 ml min-1) and in seven patients with impaired renal function (creatinine clearance 32-49 ml min-1), during thiopentone-fentanyl-midazolam-nitrous oxide-oxygen anaesthesia. Mivacurium chloride was infused at a rate of 15 μg kg-1 min-1 for 10 min, 7.5 μg kg-1 min-1 for a further 10 min, and then at a rate adjusted to maintain T1/T0 at 5%. The minimum duration of infusion was 60 min (range 60-235 min). The plasma concentration of the three isomers was measured at regular intervals throughout the infusion, and for up to 300 min after the infusion was stopped. Compartmental analysis of the resulting isomer profiles was undertaken: one- and two-compartment models were fitted to derive clearance, volume of distribution and terminal elimination half-life. Clearance of the cis-cis isomer was reduced significantly in the renal failure (median 2.4 (range 2.1-2.6) ml kg-1 min-1) and intermediate renal function groups (2.1 (2.0-2.9) ml kg-1 min-1), compared with healthy patients (3.8 (2.6-4.9) ml kg-1 min-1) (P < 0.01 in each case). There was no significant difference, within the sample size studied, between the clearance of the cis-trans isomer, in health (106 (26-147) ml kg-1 min-1), in renal failure (80 (22-135) ml kg-1 min-1) or with impaired renal function (87 (58-101) ml kg-1 min-1); or of the trans-trans isomer (57 (18-79) ml kg-1 min-1), (47 (16-88) ml kg-1 min-1) and (44 (40-55) ml kg-1 min-1), respectively). Clearance of each isomer correlated significantly with plasma cholinesterase activity (cis-trans, r = 0.55, P < 0.01; trans-trans, r = 0.62, P < 0.01), although this could be demonstrated only in healthy patients for the cis-cis isomer (r = 0.67, P < 0.05). There was no significant difference in the terminal half-lives of any isomer between the groups: cis-cis, healthy (68 (41-204) min), renal failure (80 (55-153) min), impaired renal function (101 (66-157) min); cis-trans, healthy (2.0 (1.3-4.4) min), renal failure (4.3 (2.3-7.8) min), impaired renal function (3.5 (1.4-10.4) min; trans-trans, healthy (2.3 (1.6-8.1) min), renal failure (4.2 (2.4-7.3) min), impaired renal function (13.4 (2.1-50) min). Volume of distribution was similar for each isomer in all three groups. The median infusion rate required to maintain T1/T0 at 5% was significantly increased in the impaired renal function group, at 10.0 μg kg-1 min-1, compared with both healthy patients (5.9 μg kg-1 min-1) and renal failure patients (5.0 μg kg-1 min-1) (P < 0.05 in each case).