TEMPERATURE DEPENDENCY OF THE RELEASE AND BIOAVAILABILITY OF NICOTINEFROM A NICOTINE VAPOR INHALER - IN VITRO IN VIVO CORRELATION/

Objective: To investigate the temperature dependency of the dose relea sed and the plasma levels of nicotine from a vapour inhaler. Methods: In an open, randomised, three-way cross-over pharmacokinetic study 18 healthy subjects inhaled nicotine for 20 min (80 inhalations) every ho ur for 10 h (11 administrations) at three different environmental temp eratures: 20 degrees, 30 degrees and 40 degrees C. In the in vitro exp eriment, 5, 10, 15 and 20 1 air were forced through the inhaler. With a 15 1 air volume, the average amount of nicotine released was 1.44, 3 .49, 4.80 and 6.99 mg at 10 degrees C, 22 degrees C, 29 degrees C and 40 degrees C, respectively. The maximum dose released at the highest t emperature (40 degrees C) and the largest air volume investigated (20 I) was approximately 7.5 mg. Results: In vivo peak plasma levels obtai ned at 30 degrees and 40 degrees C were 29.7 and 34.0 ng.ml(-1), compa red with 22.5 ng.ml(-1) at ambient room temperature (20 degrees C). At 20 degrees C, the area under the plasma concentration-time curve (AUG ) of the last dosing interval was 20.5 ng.ml(-1).h. At 30 degrees C an d 40 degrees C, the AUCs were 26.5 and 30.3 ng.ml(-1).h, respectively. The results thus showed a mean increase of the in vivo AUC by 29% at 30 degrees C and by 48% at 40 degrees C compared with the AUC at 20 de grees C. These increases should be compared to the in vitro results, s howing a mean increase of 59% and 122%, respectively, at 30 degrees an d 40 degrees C. The in vitro results also showed that a relatively lar ger fraction of the dose was released into the first 5 1 of air at the higher temperatures, at 40 degrees C, about 50% of the total amount r eleased into 20 1. Conclusion: It was concluded that the in vitro/in v ivo discrepancy was most probably due to increased aversive effects at elevated temperatures, causing the subjects to inhale smaller puff vo lumes. Further, the inhaler would not produce nicotine plasma levels e xceeding those achieved following cigarette smoking, even in a hot cli mate.