Pharmacokinetics and pharmacodynamics of inhaled versus intravenous morphine in healthy volunteers

Background: A new pulmonary drug delivery system produces aerosols from dis posable packets of medication. This study compared the pharmacokinetics and pharmacodynamics of morphine delivered by an AERx prototype with intraveno us morphine. Methods: Fifteen healthy volunteers were enrolled. Two subjects were admini stered four inhalations of 2.2 mg morphine each at 1-min intervals or 4.4 m g over 3 min by intravenous infusion. Thirteen subjects were given twice th e above doses, i.e., eight inhalations or 8.8 mg intravenously over 7 min. Arterial blood sampling was performed every minute during administration an d at 2, 5, 7, 10, 15, 20, 45, 60, 90, 120, 150, 180, and 240 min after admi nistration. The effect of morphine was assessed by measuring pupil diameter and ventilatory response to a hypercapnic challenge; Pharmacokinetic and p harmacodynamic analyses were performed simultaneously using mixed-effect mo dels, Results: The pharmacokinetic data after intravenous administration were des cribed by a three-exponent decay model preceded by a lag time. The pharmaco kinetic model for administration by inhalation consisted of the three-expon ent intravenous pharmacokinetic model preceded by a two-exponent absorption model. The authors found that, with administration by inhalation, the tota l bioavailability was 59%, of which 43% was absorbed almost instantaneously and 57% was absorbed with a half-life of 18 min. The median times to the h alf-maximal miotic effects of morphine were 10 and 5.5 min after inhalation and intravenous administration, respectively (P < 0.01). The pharmacodynam ic parameter k(e0) was approximately 0.003 min(-1). Conclusions: The onset and duration of the effects of morphine are similar after intravenous administration or inhalation via this new pulmonary drug delivery system. Morphine bioavailability after such administration is 59% of the dose loaded into the dosage form.