Pharmacodynamics
Of Aquavan (R) Bolus Injection: A Phase I, Dose Escalation
Comparison With Diprivan (R)
A.
Vanluchene, L. Van Bortel, J. Vornov*, E. Gibianski*, M. Struys
dep. of
Anesthesia, Ghent University, Gent, Belgium and *Guilford Pharma, Baltimore, MD,
USA
Background and Goal of Study:
AQUAVA® (AQ) (GPI 15715, Guilford Pharma., Baltimore, MD) is a water-soluble prodrug of propofol (1). This Phase I, open label, single bolus, dose escalation study compares the pharmacodynamics (PD) of propofol derived from AQ with those of DIPRIVAN® (DI) (Astra Zeneca, UK).
After IRB approval, 36 ASA I volunteers were randomized into 6 cohorts (male/female: 3/3) and given a single bolus dose of AQ (5, 10, 15, 20, 25, 30 mg/kg) within 30 s. BIS™-XP monitor (Aspect Medical Systems, Natick, MA) measured the hypnotic effect. Lowest BIS™ level (BISpeak) was recorded. One week later, DI was given to the same subjects at 50 mg/min to reach a similar BISpeak. Heart rate (HR), SpO2, and blood pressure (BP) were monitored. Incidence and duration of apnea, loss (LOC) and return (ROC) of consciousness were measured with the OAA/S score. Side effects were recorded. Statistic analysis used (un)paired non-parametric tests and Pearson correlation.
Results and Discussions
In the 5 and 10 mg/kg AQ cohorts, no LOC was observed. In the 15 mg/kg AQ cohort, 5/6 subjects reached LOC. In the 20, 25 and 30 mg/kg AQ cohorts, LOC was observed in all subjects. Similar times until LOC were seen for AQ and DI. A dose related increase in duration of unconsciousness was longer when using AQ than DI. AQ BISpeak occurred later than with DI (AQ: 623±225s; DI: 364±273, p<0.05). Pain on injection was only present with DI (12/36). With AQ, all subjects experienced a dose independent tingling sensation for 60 s after injection. Simultaneously, an initial increase in HR>90 bpm (AQ: 33/36; DI: 13/36; p<0.05) and BP was noted. With DI, early increases in BP were less pronounced with a less clear onset time. After the initial increase, a similar decrease in BP without clinically relevant hypotension was found with both drugs. Dose dependent apnea was more pronounced with DI than with AQ (AQ: 14/36; DI: 18/36).
Conclusion(s)
Bolus administration of AQ achieves LOC at a similar time as an equipotent amount of DI, but shows a slower PD. Hemodynamics were similar in both groups, except for an initial tachycardia in the AQ group. DI showed more pain on injection and apnea than AQ.
References :
Anesthesiology
2003, 99, 303-13