is administered as a single enantiomer. Duloxetine is extensively
metabolised by oxidative enzymes (CYP1A2 and the polymorphic CYP2D6),
followed by conjugation. The pharmacokinetics of duloxetine
demonstrate large intersubject variability (generally 50-60%), partly
due to gender, age, smoking status, and CYP2D6 metaboliser status.
Duloxetine is well absorbed after oral administration, with a Cmax
occurring 6 hours post- dose. The absolute oral bioavailability of
duloxetine ranged from 32% to 80% (mean of 50%). Food delays the time
to reach the peak concentration from 6 to 10 hours and it marginally
decreases the extent of absorption (approximately 11%). These changes
do not have any clinical significance.
Duloxetine is approximately 96% bound to human plasma proteins.
Duloxetine binds to both albumin and alpha1-acid glycoprotein.
Protein binding is not affected by renal or hepatic impairment.
Duloxetine is extensively metabolised and the metabolites are
excreted principally in urine. Both cytochromes P450-2D6 and 1A2
catalyse the formation of the two major metabolites, glucuronide
conjugate of 4-hydroxy duloxetine and sulfate conjugate of 5-hydroxy,
6-methoxy duloxetine. Based upon in vitro studies, the circulating
metabolites of duloxetine are considered pharmacologically inactive.
The pharmacokinetics of duloxetine in patients who are poor
metabolisers with respect to CYP2D6 has not been specifically
investigated. Limited data suggest that the plasma levels of
duloxetine are higher in these patients.
The elimination half-life of duloxetine ranges from 8 to 17 hours
(mean of 12 hours). After an intravenous dose the plasma clearance of
duloxetine ranges from 22 l/hr to 46 l/hr (mean of 36 l/hr). After an
oral dose the apparent plasma clearance of duloxetine ranges from 33
to 261 l/hr (mean 101 l/hr).
Pharmacokinetic differences have been identified between males and
females (apparent plasma clearance is approximately 50% lower in
females). Based upon the overlap in the range of clearance,
gender-based pharmacokinetic differences do not justify the
recommendation for using a lower dose for female patients.
Pharmacokinetic differences have been identified between younger and
elderly females (≥65 years) (AUC increases by about 25% and
half-life is about 25% longer in the elderly), although the magnitude
of these changes is not sufficient to justify adjustments to the
dose. As a general recommendation, caution should be exercised when
treating the elderly.
impairment: End stage renal disease (ESRD) patients receiving
dialysis had 2-fold higher duloxetine Cmax and AUC values
compared with healthy subjects. Pharmacokinetic data on duloxetine is
limited in patients with mild or moderate renal impairment.
impairment: Moderate liver disease (Child-Pugh Class B) affected
the pharmacokinetics of duloxetine. Compared with healthy subjects,
the apparent plasma clearance of duloxetine was 79% lower, the
apparent terminal half-life was 2.3-times longer, and the AUC was
3.7-times higher in patients with moderate liver disease. The
pharmacokinetics of duloxetine and its metabolites have not been
studied in patients with mild or severe hepatic insufficiency.
mothers: The disposition of duloxetine was studied in 6 lactating
women who were at least 12-weeks postpartum. Duloxetine is detected
in breast milk, and steady-state concentrations in breast milk are
about one-fourth those in plasma. The amount of duloxetine in breast
milk is approximately 7µg/day while on 40 mg twice-daily
dosing. Lactation did not influence duloxetine pharmacokinetics.
population: Pharmacokinetics of duloxetine in paediatric patients
aged 7 to 17 years with major depressive disorder following oral
administration of 20 to 120 mg once daily dosing regimen was
characterized using population modelling analyses based on data from
3 studies. The model-predicted duloxetine steady-state plasma
concentrations in paediatric patients were mostly within the
concentration range observed in adult patients.
[Summary of Product Characteristics]. Utrecht, The Netherlands: Eli
Lilly Nederland B.V.