Pharmacodynamics and pharmacokinetics of an infusion of Org 9487, a new short-acting steroidal neuromuscular blocking agent

Abstract

We have evaluated in 10 anaesthetized patients the time course of action, infusion requirements, reversibility and pharmacokinetics of Org 9487. Org 9487 was administered as a bolus dose of 1.5 mg kg-1, followed by an infusion to maintain a block of 75-85% for 60 min. After recovery from the bolus dose, a mean dose of Org 9487 3.4 (SD 1.0) mg kg-1 h-1 was administered to maintain a mean neuromuscular block of 83 (3)%. During the final 15 min of infusion, the infusion requirements were 2.5 (1.1) mg kg-1 h-1. In the five patients who were allowed to recover spontaneously, a TOF ratio of 0.7 was reached 37.9 (12.4) min after stopping the infusion of Org 9487. In the five patients who received neostigmine, a TOF ratio of 0.7 was reached after 14.5 (6.1) min. Plasma clearance was 8.5 (30%) ml kg-1 min-1. Volume of distribution at steady state was 293 (55%) ml kg-1. Terminal half-life and mean residence time were 71.7 (34%) and 33.4 (31%) min, respectively. The concentration of the 3-OH metabolite remained relatively low. Urinary excretion of Org 9487 and its metabolites was 22% in 24 h. In conclusion, a 1-h infusion of the short-acting drug Org 9487 changed its time course characteristics gradually from that of a short-acting neuromuscular blocking agent to that of a neuromuscular blocker with an intermediate duration of action.

Cumulation characteristics of cisatracurium and rocuronium during continuous infusion

“…As a guide to therapy, infusion requirements of the newer intermediate duration relaxants cisatracurium (CIS) and rocuronium (ROC) have been established. [2][3][4][5][6][7][8][9] However, despite wide inter-patient variability in drug requirements, previous studies have not specifically addressed how infusion rates need to be adjusted as a function of time, during the conduct of anesthesia.…”

“…However, ROC also has a considerably longer elimination half-life than CIS (t 1/2 ß=60-70 min for ROC, 22-26 min for CIS). 4,7 The present study was therefore designed to compare the time to onset of action, time-related infusion requirements, drug costs, and cumulation potential of CIS vs ROC during procedures of relatively long duration.…”

Rapacuronium: clinical pharmacology

“…studies also confirmed the rapid reversibility of the effects of rapacuronium, the times taken to achieve adequate antagonism were generally somewhat longer, particularly with higher doses; this may have been due to the dosage of the drug administered being based on the active moiety. The reduction of dose for maintenance of constant block and the prolonged recovery after a 1-h infusion of rapacuronium suggested the presence of cumulative properties with rapacuronium [21]. This is in contrast to mivacurium, where administration of an antagonist shortens the recovery time only slightly and insignificantly [19].…”

Muscle relaxants in paediatric day case surgery

“…It is metabolized in the liver primarily to a 3-hydroxy metabolite (Org 9488), which itself is a neuromuscular blocking drug, having twice the potency of rapacuronium (biophase EC 50 0.4 Â rapacuronium) and an intermediate to long duration of action [31]. Excretion of rapacuronium and its metabolites is organ dependent and there is some evidence of cumulation of Org 9488 after repeated doses or an infusion [32].…”