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PHARMACOKINETIC PROFILE OF AV430A IN HUMAN VOLUNTEERS

New York Presbyterian Hospital-Cornell Medical Center, 525 East 68^th Street, New York, NY 10021, USA

INTRODUCTION: AV430A is a new nondepolarizing alpha-chlorofumarate neuromuscular blocking drug with a rapid onset and short duration of action. This study was conducted to evaluate the pharmacokinetic profile of this drug in volunteers.

METHODS: After IRB approval, ten ASA 1 male and female volunteers aged 22–45 yrs were studied in 2 groups of five as part of a larger volunteer study of AV430A. Anesthesia was induced with midazolam, fentanyl, and propofol and maintained with N₂O/O₂ 70%/30%, propofol and fentanyl as needed. BP, HR, ECG, ETCO₂, and temperature were monitored in the standard manner. The ulnar nerve was stimulated at the wrist with train-of-four every 10s and MMG responses of the adductor pollicis were recorded. The first group of five volunteers received 0.19mg/kg AV430A (1.5XED95) followed by a 30-minute infusion upon evidence of return of the twitch. The infusions were maintained to provide 95±4% twitch suppression. Arterial blood samples were collected prior to the bolus, 30s and 60s after the bolus, immediately prior to starting infusion, and 30s, 1, 2, 3, 4, 5, 15, 30, 31, 31.5, 32, 33, 34, 36, 38, 42, 50, and 60 min after start of the infusion. The second group of five volunteers received a single bolus of 0.625mg/kg AV430A (5XED95) and had 12 arterial blood samples collected prior to the bolus, 30s, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, and 20 min after. Analysis of concentration-time data was conducted by non-compartmental analysis using WinNonlin. AV430A concentrations at 15 and 30 minutes during infusion were assumed to represent steady-state. Blood clearance (CL_B) was estimated from average steady state concentration (C_ss,avg) as follows: CL_B=infusion rate/C_ss,avg.

RESULTS: The average rate of infusion ranged from 58–62mcg/kg/min. The terminal elimination half-life of AV430A at the termination of infusion was 3.09±0.21 min and the C_ss,avg was 3126±923 ng/ml. CL_B was 20.2±4.7 ml/min/kg. After the single bolus dose the elimination half-life was 2.41±0.17 min with an average CL_B=22.1± 5.9 ml/min/kg. The estimated volumes of distribution at steady state and terminal phase averaged 0.057±0.024 L/kg and 0.077±0.021 L/kg.

DISCUSSION: The elimination half-life and blood clearance of AV430A are very similar when the agent is administered either as a bolus of 5XED95 or an infusion that maintained 95% block. AV430A is not widely distributed. The pharmacokinetic parameters are consistent with in situ rapid inactivation by plasma cysteine with a resultant short acting pharmacodynamic profile.

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