STIOLTO RESPIMAT
When STIOLTO RESPIMAT was
administered by the inhalation route, the pharmacokinetic parameters
for tiotropium and for olodaterol were similar to those observed when
each active substance was administered separately.
Tiotropium
Tiotropium is administered as an inhalation spray. Some of the pharmacokinetic
data described below were obtained with higher doses than recommended
for therapy.
Olodaterol
Olodaterol showed linear pharmacokinetics.
On repeated once-daily inhalation, steady-state of olodaterol plasma
concentrations was achieved after 8 days, and the extent of exposure
was increased up to 1.8-fold as compared to a single dose.
Absorption
Tiotropium
Following inhalation
of the solution by young healthy volunteers, urinary excretion data
suggests that approximately 33% of the inhaled dose reaches the systemic
circulation. Oral solutions of tiotropium have an absolute bioavailability
of 2% to 3%. Food is not expected to influence the absorption of tiotropium
for the same reason. Maximum tiotropium plasma concentrations were
observed 5 to 7 minutes after inhalation.
Olodaterol
Olodaterol
reaches maximum plasma concentrations generally within 10 to 20 minutes
following drug inhalation. In healthy volunteers the absolute bioavailability
of olodaterol following inhalation was estimated to be approximately
30%, whereas the absolute bioavailability was below 1% when given
as an oral solution. Thus, the systemic availability of olodaterol
after inhalation is mainly determined by lung absorption, while any
swallowed portion of the dose only negligibly contributes to systemic
exposure.
Distribution
Tiotropium
The drug has a plasma protein binding of 72% and shows a volume
of distribution of 32 L/kg. Local concentrations in the lung are not
known, but the mode of administration suggests substantially higher
concentrations in the lung. Studies in rats have shown that tiotropium
does not penetrate the blood-brain barrier.
Olodaterol
Olodaterol
exhibits multi-compartmental disposition kinetics after inhalation
as well as after intravenous administration. The volume of distribution
is high (1110 L), suggesting extensive distribution into tissue. In vitro binding of [14C] olodaterol to human plasma proteins
is independent of concentration and is approximately 60%.
Elimination
Metabolism
Tiotropium
The extent of metabolism is small. This is evident from
a urinary excretion of 74% of unchanged substance after an intravenous
dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically
cleaved to the alcohol N-methylscopine and dithienylglycolic acid,
both not binding to muscarinic receptors.
In vitro experiments with
human liver microsomes and human hepatocytes suggest that a fraction
of the administered dose (74% of an intravenous dose is excreted unchanged
in the urine, leaving 25% for metabolism) is metabolized by cytochrome
P450-dependent oxidation and subsequent glutathione conjugation to
a variety of Phase 2 metabolites. This enzymatic pathway can be inhibited
by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole,
and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic
pathway that is responsible for the elimination of a small part of
the administered dose. In vitro studies using human
liver microsomes showed that tiotropium in supra-therapeutic concentrations
does not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.
Olodaterol
Olodaterol is substantially metabolized by direct glucuronidation
and by O-demethylation at the methoxy moiety followed by conjugation.
Of the six metabolites identified, only the unconjugated demethylation
product binds to beta2-receptors. This metabolite,
however, is not detectable in plasma after chronic inhalation of the
recommended therapeutic dose.
Cytochrome P450 isozymes CYP2C9 and CYP2C8,
with negligible contribution of CYP3A4, are involved in the O-demethylation
of olodaterol, while uridine diphosphate glycosyl transferase isoforms
UGT2B7, UGT1A1, 1A7, and 1A9 were shown to be involved in the formation
of olodaterol glucuronides.
Excretion
Tiotropium
The terminal half-life of tiotropium
in COPD patients following once daily inhalation of 5 mcg tiotropium
was approximately 25 hours. Total clearance was 880 mL/min after an
intravenous dose in young healthy volunteers. Intravenously administered
tiotropium bromide is mainly excreted unchanged in urine (74%). After
inhalation of the solution by patients with COPD, urinary excretion
is 18.6% (0.932 mcg) of the dose, the remainder being mainly non-absorbed
drug in the gut that is eliminated via the feces. The renal clearance
of tiotropium exceeds the creatinine clearance, indicating secretion
into the urine. After chronic once-daily inhalation by COPD patients,
pharmacokinetic steady state was reached by day 7 with no accumulation
thereafter.
Olodaterol
Total clearance of olodaterol in healthy
volunteers is 872 mL/min, and renal clearance is 173 mL/min. The terminal
half-life following intravenous administration is 22 hours. The terminal
half-life following inhalation in contrast is about 45 hours, indicating
that the latter is determined by absorption rather than by elimination
processes. However, the effective half-life at daily dose of 5 mcg
calculated from Cmax from COPD patients is
7.5 hours.
Following
intravenous administration of [14C]-labeled olodaterol, 38% of the
radioactive dose was recovered in the urine and 53% was recovered
in feces. The amount of unchanged olodaterol recovered in the urine
after intravenous administration was 19%. Following oral administration,
only 9% of olodaterol and/or its metabolites was recovered in urine,
while the major portion was recovered in feces (84%). More than 90%
of the dose was excreted within 6 and 5 days following intravenous
and oral administration, respectively. Following inhalation, excretion
of unchanged olodaterol in urine within the dosing interval in healthy
volunteers at steady state accounted for 5% to 7% of the dose.
Drug Interactions
STIOLTO RESPIMAT
Pharmacokinetic
drug interaction studies with STIOLTO RESPIMAT have not been performed;
however, such studies have been conducted with individual components
tiotropium and olodaterol.
When tiotropium and olodaterol were administered
in combination by the inhaled route, the pharmacokinetic parameters
for each component were similar to those observed when each active
substance was administered separately.
Tiotropium
An
interaction study with tiotropium (14.4 mcg intravenous infusion over
15 minutes) and cimetidine 400 mg three times daily or ranitidine
300 mg once-daily was conducted. Concomitant administration of cimetidine
with tiotropium resulted in a 20% increase in the AUC0-4h, a 28% decrease in the renal clearance of tiotropium and no significant
change in the Cmax and amount excreted in urine
over 96 hours. Co-administration of tiotropium with ranitidine did
not affect the pharmacokinetics of tiotropium.
Common concomitant medications (long-acting
beta2-adrenergic agonists (LABA), inhaled corticosterioids
(ICS)) used by patients with COPD were not found to alter the exposure
to tiotropium.
Olodaterol
Drug-drug interaction studies were
carried out using fluconazole as a model inhibitor of CYP 2C9 and
ketoconazole as a potent P-gp (and CYP3A4, 2C8, 2C9) inhibitor.
Fluconazole: Co-administration of 400 mg fluconazole once a day for 14 days
had no relevant effect on systemic exposure to olodaterol.
Ketoconazole: Co-administration of 400 mg
ketoconazole once a day for 14 days increased olodaterol Cmax by 66% and AUC0-1 by 68%.
Tiotropium: Co-administration of tiotropium
bromide, delivered as a fixed-dose combination with olodaterol, for
21 days had no relevant effect on systemic exposure to olodaterol,
and vice versa.
Specific Populations
Olodaterol
A pharmacokinetic meta-analysis showed that no dose adjustment
is necessary based on the effect of age, gender, and weight on systemic
exposure in COPD patients after inhalation of olodaterol.
Geriatric Patients
Tiotropium
As expected for
all predominantly renally excreted drugs, advancing age was associated
with a decrease of tiotropium renal clearance (347 mL/min in COPD
patients <65 years to 275 mL/min in COPD patients ≥65 years). This
did not result in a corresponding increase in AUC0-6,ss and Cmax,ss values.
Renal Impairment
Tiotropium
Following inhaled administration
of therapeutic doses of tiotropium to steady-state to patients with
COPD, mild renal impairment (creatinine clearance 60 - <90 mL/min)
resulted in 23% higher AUC0-6,ss and 17% higher
Cmax,ss values. Moderate renal impairment
(creatinine clearance 30 - <60 mL/min) resulted in 57% higher AUC0-6,ss and 31% higher Cmax,ss values
compared to COPD patients with normal renal function (creatinine clearance >90 mL/min). In COPD patients with severe renal impairment
(CLCR <30 mL/min), a single intravenous administration of tiotropium
bromide resulted in 94% higher AUC0-4 and 52%
higher Cmax compared to COPD patients with
normal renal function.
Olodaterol
Olodaterol levels were increased
by approximately 40% in subjects with severe renal impairment. A study
in subjects with mild and moderate renal impairment was not performed.
Hepatic Impairment
Tiotropium
The effects of
hepatic impairment on the pharmacokinetics of tiotropium were not
studied.
Olodaterol
Subjects with mild and moderate hepatic impairment showed
no changes in Cmax or AUC, nor did protein
binding differ between mild and moderate hepatically impaired subjects
and their healthy controls. A study in subjects with severe hepatic
impairment was not performed.
