Jb. Lecaillon et al., Pharmacokinetics and tolerability of formoterol in healthy volunteers after a single high dose of foradil dry powder inhalation via Aerolizer (TM), EUR J CL PH, 55(2), 1999, pp. 131-138
Objective. The pharmacokinetics of the long-acting beta(2)-agonist formoter
ol fumarate, which is a racemate of the (S,S)- and (R,R)-enantiomers were e
valuated in 12 healthy (eight male, four female) volunteers after a single
inhaled high dose of 120 mu g of formoterol fumarate. The tolerability and
safety were also assessed.
Methods: Each volunteer inhaled the single 120-mu g dose through the Aeroli
zer device within 2-5 min, using ten 12-mu g dry powder capsules for inhala
tion. Formoterol, i.e., the sum of both enantiomers, was determined in plas
ma over 24 h, whereas the separate enantiomers were determined in urine ove
r 48 h. Incidence, seriousness and severity of adverse experiences, electro
cardiogram (ECG), including the corrected QT interval (QTc) calculation, sy
stolic blood pressure, heart rate, and plasma potassium levels were recorde
d.
Results: In nine of the 12 volunteers, the peak plasma concentration of for
moterol was observed already at 5 min after inhalation. The absorption kine
tics were complex, as depicted by multiple peaks or shoulders within 0.5-6
h after inhalation. Mean with (SD; n = 12) Of maximum concentration (C-max)
and area under the curve (AUC) of formoterol in plasma were 266 (108) pmol
. l(-1) and 1330 (398) pmol h . l(-1), respectively. The moderate inter-in
dividual variability in systemic exposure of formoterol reflects the homoge
neous pharmacokinetics of the drug. A predominant slow elimination of formo
terol from plasma with a mean half-life (t(1/2)) Of 10 h was demonstrated.
Assuming linear kinetics in plasma suggested by urinary data, the steady-st
ate trough plasma levels of formoterol for a b.i.d. dosing regimen are pred
icted to amount to 20% of C-max. In urine, mean with (SD; n = 10) of the am
ount excreted over 45 h was 3.61 (0.89)% of dose for the pharmacologically
active (R,R)-enantiomer and 4.80 (1.33)% of dose for the (S,S)-enantiomer.
The terminal half-lives calculated from the excretion rate-time curves, i.e
., 13.9 h and 12.3 h for the (R,R)- and (S,S)-enantiomer, respectively, con
firm the slow elimination of formoterol from plasma. The dose inhaled was 1
0 times the most frequently recommended dose (12 mu g) and 5 times the high
est recommended dose (24 Gig). Ten of 12 subjects experienced mild and tran
sient nervousness. Pulse readings demonstrated the maximum mean increase of
25.8 beats . min(-1) at 6 h. The mean maximum QTc increase was 25 msec at
6 h. Pulse and QTc values returned to baseline or close to baseline values
at 24 h or before. Potassium levels in plasma decreased in eight out of 12
subjects; the lowest mean value was 3.53 mmol l(-1) at 2 h post-dose. The l
owest individual potassium measurement was 2.95 mmol . l(-1) between 15 min
and 6 h. By 8 h postdose all values had returned to within the normal rang
es.
Conclusions: The extremely fast appearance of formoterol in plasma shows th
e predominance of airways absorption shortly after inhalation. Due to a ter
minal elimination half-life of about 10 h, sustained systemic concentration
s of formoterol are predicted for a twice daily treatment regimen without n
oteworthy accumulation. The excreted amounts in percent of dose of the enan
tiomers in urine and the enantiomer ratio are similar to data reported prev
iously after lower doses and suggest linear kinetics for doses between 12 m
u g and 120 mu g of formoterol fumarate. The expected side effects on heart
rate, QTc interval, and plasma potassium were small and had no clinical co
nsequences in spite of the very high close of 120 mu g (5 to 10 times the r
ecommended therapeutic dose of Foradil). It should be noted that the impact
of high doses may be greater in patients. Nevertheless these findings prov
ide reassurance on the safety margin of formoterol after accidental and int
entional overdosing.