CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
BRIEFING DOCUMENT
|
NDA |
21-395 |
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Tiotropium bromide
Inhalation Powder |
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Drug Product |
Spiriva“ Inhalation Powder |
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Strengths |
18 mg per capsule |
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Route of Administration |
Oral Inhalation |
|
Sponsor |
Boehringer Ingelheim
Pharmaceuticals, Inc. |
|
Type of submission |
NME, 1S |
|
Date of submission |
12/12/01 |
|
OCPB Division |
DPE-II |
|
Clinical Division |
Pulmonary and Allergy Drug
Products (HFD-570) |
1. EXECUTIVE
SUMMARY
Tiotropium bromide
monohydrate is an anticholinergic drug with specificity for muscarinic
receptors, proposed to be used for the long-term, once-daily, maintenance
treatment of bronchospasm and dyspnea associated with chronic obstructive
pulmonary disease (COPD), including chronic bronchitis and emphysema. The proposed dosage of tiotropium is
inhalation of the contents of one capsule (18 mg of
tiotropium cation), once daily, with the HandiHaler inhalation device.
Pharmacokinetic data for
tiotropium were obtained from 15 clinical studies in a total of 600
subjects. In addition, many in vitro studies (metabolism pathways,
stability of tiotropium, protein binding) were performed to support this
NDA. Pharmacokinetic characteristics of
tiotropium in humans are summarized below.
The absolute bioavailability
of tiotropium after dry powder inhalation is 19.5% and negligible after oral
administration (2-3%). The drug is
extensively distributed in the body and has a volume of distribution of 32
L/kg. The apparent terminal elimination
half-life is between 5 and 6 days. An
approximate steady state is achieved within 2-3 weeks by inhalation of 18 mg dry powder inhalation capsules and steady state plasma concentrations
are about two times higher than concentrations after a single dose. Tiotropium plasma concentrations after an 18
mg inhalation range in steady state between a minimum
of 2-4 pg/mL and a maximum of 15-20 pg/mL.
Tiotropium is eliminated by renal excretion (73.6% of dose as parent
compound in young healthy subjects) with a renal clearance exceeding the
creatinine clearance, which suggests an active secretion by the kidney. Some of the drug (<30%) undergoes
nonenzymatic ester cleavage as well as metabolism. As expected for any mainly renally eliminated drug, there is an
increase of systemic exposure in subjects with renal dysfunction and thus also
a slight increase in advanced age.
Drug-drug interactions by tiotropium on other drugs are not expected due
to the low dose of 18 mg and the lack of cytochrome P450 inhibition by
tiotropium shown in in vitro
studies. Since elimination of
tiotropium by metabolism is minor, metabolic interactions of tiotropium are not
expected.
During the drug development,
the formulation was changed a few times (Phase I, II and III
formulations). Also, the device that
delivers the dry powder inhalation capsule was changed from the Inhalator
Ingelheim (FO2) device to the HandiHaler device. Although a developmental formulation and device were used in
dose-ranging studies, the to-be marketed formulation (Phase III formulation)
and device (HandiHaler) were used in the Phase III studies and pivotal Phase I
studies.
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1 EXECUTIVE
SUMMARY
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1 |
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2 TABLE OF
CONTENTS
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3 |
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3 SUMMARY OF OCPB
FINDINGS
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4 |
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4 QUESTION BASED REVIEW
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7 |
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4.1. General
Attributes
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7 |
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7 8 |
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4.2. General Clinical
Pharmacology
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8 |
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8 |
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4.2.2 Are
the active moieties in the plasma appropriately identified and measured to
assess PK parameters and exposure response relationship?
... |
9 |
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4.2.3 What
are the characteristics of the exposure-response relationships
(dose-response, concentration-response) for efficacy and safety? Based on PK parameters, what is the degree
of linearity or non-linearity in the dose-concentration relationship? Do PK parameters change with time
following chronic dosing? How long is the time to the onset and offset of the
pharmacological response or clinical endpoints? Are the dose and dosing regimen consistent with the known
relationship between dose-concentration-response, and are there any
unresolved dosing or administration issues?.
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11 |
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4.2.4 How does the PK of tiotropium in healthy
volunteers compared to that in patients following dry powder
inhalation? What are the basic PK
parameters? Is this a high extraction ratio or a low
extraction ratio drug?
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15 |
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15 |
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4.3. Intrinsic Factors
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15 |
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4.3.1 What
are the relevant covariates that the pharmacokinetic variability of
tiotropium?
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15 |
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4.4.
Extrinsic Factors
... |
18 |
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18 18 19 19 |
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4.5 General
Biopharmaceutics
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20 |
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permeability and dissolution data
support this classification?
.. 4.5.2 Has the proposed commercial formulation
and device been adequately linked to the Phase III
clinical trial formulation and device?
... |
20 20 |
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dosing recommendation should be
made, if any regarding administration of the product in relation to meals or meal
type?
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21 |
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4.6
Analytical
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21 |
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4.6.1 Were the analytical procedures used to
determine drug concentrations in this NDA acceptable? |
21 |
3. Summary of Clinical
Pharmacology and Biopharmaceutics Findings
Absorption: Tiotropium
is a quaternary amine and it is not readily absorbed into the systemic
circulation after oral administration of aqueous solutions as confirmed by the
low bioavailability of 2-3% in young healthy subjects, while tiotropium showed
an absolute bioavailability of 19.5% after dry powder inhalation in these
subjects.
Plasma
profiles of tiotropium showed a rapid absorption and distribution with tmax at 5 min post inhalation (first sampling time), then,
tiotropium plasma concentrations declined rapidly and 2-4 hours after
inhalation they are often no longer quantifiable. Geometric mean tiotropium plasma concentrations 5 minutes after a
first inhalation (C5min) of 18 ΅g were often below the limit of
quantification (3-5 pg/mL), while observed C5min of 17-19 pg/mL after multiple doses.
There was a
trend to increased plasma concentrations with higher doses, which suggest the
deviant behavior from the linear dose proportionality. However, the linearity of PK could not be
confirmed due to insufficient data.
Distribution: 72% of
tiotropium is bound to human plasma.
The volume of distribution (Vss) after a 14.4 ΅g intravenous infusion was 32 L/kg
(205.105). This high Vss indicates an extensive tissue binding of the drug.
Metabolism: Tiotropium
is predominantly eliminated via renal secretion of unchanged drug (73.6% of
dose as a parent drug was recovered in urine after intravenous infusion in
healthy young male subjects). The fate
of the remaining quarter of the dose in subjects is not exactly known.
Metabolism
was investigated in in vitro studies
and in vivo animal studies. In
vitro studies indicated that (1) hydrolytic cleavage of the ester bond of
tiotropium occurs non-ezamatically (converted to N-methylscopine and
dithienylglycolic acid). (2)
N-methylscopine and other metabolites (a variety of glutathione conjugates
after oxidation of the thiophen ring system) were formed enzymatically via CYP
2D6 and probably CYP 3A4. (3)
N-methylscopine and dithienylglycolic acid are pharmacologically inactive, and
(4) high tiotropium concentrations of 1 ΅mol/L did not inhibit cytochrome P450
1A1, 1A2, 2B1, 2C9, 2C19, 2D6, 2E1, or 3A4.
Elimination: In healthy young male subjects, urinary
excretion of unchanged drug accounted for 73.6% and 14.4% of the dose after an
intravenous infusion and dry powder inhalation, respectively. Total clearance was 880 mL/min with a renal
clearance (CLr) of 669 mL/min after intravenous infusion. CLr was 486 mL/min after inhalation. Renal clearance is greater than the
creatinine clearance, which suggests that tiotropium under goes active renal
secretion. It is not known which cation
transporter is responsible for the active renal secretion but in vitro investigations in CaCo2 cells
showed that it is probably not p-glycoprotein.
Tiotropium excreted in urine after chronic once daily inhalation by COPD
patients was about 7 % and the steady state was reached after 2-3 weeks in
these patients. The terminal
elimination half-life of tiotropium is between 5 and 6 days following
inhalation. The high renal clearance as
well as the urinary recovery of about 73.6% (intravenous) as unchanged
substance indicates that the long elimination half-life may be due to a slow
redistribution process.
PK/PD
relationship: None of the
clinical studies related the responses (efficacy or safety) to the
pharmacokinetics of tiotropium. An Emax model established from dose-response (FEV1) relationship data obtained from Phase II studies was
arrived to select the dose for Phase III studies. Time-response plots were made using the data from studies with a
single escalating inhalation doses. A
second peak was seen at around 24 hrs in these studies. The reason of this 2nd peak is not known, however, it does not appear to be
due to pharmacokinetic characteristics of tiotropium (i.e., no active
metabolites, no enterohepatic recirculation).
It could be, as the sponsor suggested, due to circadian rhythm.
Pharmacokinetics in special populations
Gender
effect: Male and
female COPD and asthma patients showed no relevant differences in drug plasma
concentrations or urinary excretion of tiotropium.
Age Effect: Renal
clearance was significantly decreased to 326 mL/min in COPD patients with a
geometric mean age of 53 years to 163 mL/min (50% decrease) in patients with an
mean age of 74 years following 18 mg by inhalation.
The decrease in urinary excretion was associated with an increase of AUC0-4h values from 18.2 pg∑h/mL (69% gCV) to 26.1 pg∑h/mL (63% gCV) at the same time (~40% increase). However, a dose adjustment in advanced age
is not considered necessary, because COPD patients of this age range are the
target population, which was consequently studied regarding safety and
efficacy.
Patients
with renal impairment: Following an
intravenous dose of 4.8 mg in healthy volunteers, tiotropium plasma concentrations
increased with renal dysfunction with more pronounced changes in subjects with
a CLcr < 50 mL/min; tiotropium AUC0-4h were 39, 81 and 94% higher in mild (CLcr >50-80
mL/min), moderate (CLcr >30-50 mL/min), and severe (CLcr <30 mL/min)
renal impairment when compared to control subjects. The effect of a renal insufficiency on tiotropium concentrations
after inhalation in COPD patients was also evaluated in Study 205.117. Trough plasma concentrations (C-5min) at steady state (Day 92) increased by about 10% and
27% in mild and moderate impairment, respectively, compared to patients with
normal renal function. C5min,ss (Day 92) increased by 84% and 188% in mild and moderate
impairment, respectively, compared to patients with normal renal function. Increase of plasma concentrations was
associated with a decrease of 20% and 50% in Ae0-24h, ss mild and moderate renal impairment, respectively,
compared to patients with normal renal function. Therefore, tiotropium should be used with caution in patients
with renal impairment, especially those with moderate and severe impairment.
Patients
with hepatic impairment: The effect
of hepatic impairment was not studied in human. Tiotropium was predominantly cleared by renal elimination as a
parent drug (~70% in healthy young subjects), therefore, approximately 30% of
dose (part of dose are degraded by ester cleavage) are expected to be
eliminated as a metabolites. Thus,
based on minor elimination by a metabolism route and low tiotropium plasma
concentrations after 18 ΅g inhalation dose, a clinically significant effect due
to hepatic dysfunction is not anticipated.
Effect of
COPD and asthma: The effect
of the pulmonary disease on the absorbed fraction of the inhaled dose is not
exactly known, because this effect is hard to separate from the confounding
effects of age and formulation on the urinary excretion.
Drug-drug
interactions: Less than
30% of tiotropium dose is expected to be metabolized by cytochrome CYP 2D6 and
probably CYP 3A4. Therefore, potential
interactions with the inhibitors of these two enzymes (e.g., quinidine,
gestodene, ketoconazole) are expected.
No clinical studies have been performed to evaluate these
interactions. However, based on the low
extent of overall metabolism of the drug (<30%) and low tiotropium plasma
concentrations (0.01 and 0.05 nmol/L) after a dose of 18 ΅g dry powder
inhalation, a clinically significant metabolic interaction is not
anticipated. Higher tiotropium plasma
concentrations are expected in the 2D6 poor metabolizers. Indeed AUC0-4h was 33% higher in the poor 2D6 metabolizers (there
were 4 subjects in the Study 205.222) in comparison to the extensive 2D6
metabolizers, however, this change does not warrant the lower dosing
regimen. In addition, in vitro metabolic study showed that high tiotropium concentrations of 1
΅mol/L did not inhibit cytochrome P 450 1A1, 1A2, 2B1, 2C9, 2C19, 2D6, 2E1, or
3A4 in human liver microsomes.
As many
cationic drugs, tiotropium is actively secreted into urine, therefore, there is
a possible interaction with drugs which are also actively secreted into
urine. However, there were no
clinically significant changes in pharmacokinetics of tiotropium when
cimetidine (400-mg tid) or ranitidine (300 mg qd) was co-administered with
tiotropium.
Food effect:
Clinificantly significant food effects are not expected for this
hydrophilic drug with its low oral bioavailability of 2-3%.
Formulation development: Formulation
of a dry powder inhalation capsule was changed (Phase I, II and III
formulation) along with inhalation devices during the drug development. Dose finding trial (Study 205.108) used a
developmental formulation and device (i.e., Phase II formulation with FO2
device) was used, but the to-be marked formulation with the intended device
(i.e., Phase III formulation with HandiHaler) was used in Phase III and pivotal
Phase I studies. In Study 205.108, the
urinary excretion was lower compared to that in Phase III study, such as Study
205.117 (approximately Ae0-24h of 4.5 vs.
7% of dose).
Analytical Methods: Tiotropium
was quantified by the validated LC-MS/MS methods. The assay method was acceptable in terms of sensitivity and
selectivity.
4. Question Based Review
4.1 General Attributes
4.1.1 What are the highlights of the chemistry and
physical-chemical properties of the drug substance, and the formulation of the
drug product? What is the proposed
mechanism of drug action and therapeutic indications? What is the proposed dosage and route of administration?
SPIRIVA‘ consists of a hard gelatin capsule containing a dry
powder for use with the HandiHaler“ inhalation device.
Each hard gelatin capsule contains 18 mg tiotropium (equivalent to 22.5 mg tiotropium bromide monohydrate) blended with lactose
monohydrate as the carrier. The drug
substance, tiotropium bromide (monohydrate) has a molecular mass of 490.4 and a
molecular formula of C19H22NO4S2Br∑H2O. It is
sparingly soluble in water and soluble in methanol, and has the following
structural formula:
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Tiotropium
bromide is developed as a long-acting anticholinergic bronchodilator, around 24
hrs of duration of action (in vitro study showed that tiotropium binds
to all five muscarinic receptor subtypes and the dissociation from the m3 receptor seems to be slower than from m1 and m2 receptors).
Ipratropium bromide is currently on the market as a short acting (6
hours of duration of action) bronchodilator.
Tiotropium bromide is intended for the long-term maintenance treatment
of bronchospasm and dyspnea associated with COPD including chronic bronchitis
and emphysema with one capsule inhalation powder once-daily dosing
regimen.
4.1.2. What efficacy and safety information (e.g.,
biomarkers, surrogate endpoints, and clinical endpoints) contribute to the
assessment of clinical pharmacology and biopharmaceutics study data (e.g., if
disparate efficacy measurements or adverse event reports can be attributed to
intrinsic or extrinsic factors that alter drug exposure/response relationships
in patients)?
Data from a
study in asthma patients provided urinary excretion rates over a broader range
of FEV1 baseline values and suggested some minor influence of
the disease severity on the urinary excretion (decreasing excretion with
increasing severity). This effect was
also evaluated in COPD patients of different disease severity. There was no consistent effect of the
decrease in lung function on tiotropium plasma concentrations or on the urinary
excretion of tiotropium. Overall, the
effect of the chronic pulmonary disease on the absorbed fraction of the inhaled
dose is not exactly known, because this effect is hard to separate from the
confounding effects of age on the urinary excretion.
4.2. General
Clinical Pharmacology
4.2.1 What is the basis for selecting the clinical-response
endpoints (i.e., clinical or surrogate endpoints or biomarkers) and how are
they measured in clinical pharmacology and clinical studies?
The clinical
pharmacology of tiotropium was evaluated in 22 completed clinical trials
(reviewed 15 studies which contained the PK). The tolerability and
bronchoactive properties of tiotropium in relation to dose were evaluated in
healthy volunteers, COPD patients and asthma patients.
Efficacy variables: Tiotropium is
an anticholinergic bronchodilator. The
effects of tiotropium is evidenced by improvements in FEV1 (Forced Expiratory Volume in one second), FVC (Forced
Vital Capacity), PEER (Peak Expiratory Flow Rate) or decrease in airway
resistance (Raw). In the
clinical trials, the bronchodilator efficacy of inhaled tiotropium was
primarily determined by trough FEV1 response;
defined as change from base line in trough FEV1; trough FEV1 was calculated as the mean of the two FEV1 readings prior to the first administration of study
medication and at the end of the dosing interval. Secondary endpoints include FVC, PEER, Raw, PEFRs, COPD/asthma symptoms, physicians global
evaluation, albuterol rescue use, oral and inhaled steroid use, theophylline
use, the number of awakenings, Baseline and Transitional Dyspnea Index, and
quality of life measures. To assess the
quality of life, the Impact score from the St. Georges Hospital Respiratory
Questionnaire (SGRQ) was used.
Safety Measures: Adverse
events, fluctuation in the patients COPD/asthma symptoms, Clinical and
laboratory tests, ECG and vital signs were monitored.
4.2.2 Are the
active moieties in the plasma (or other biological fluid) appropriately
identified and measured to assess PK parameters and exposure response
relationships?
Only the
parent compound, tiotropium, was measured in the plasma and urine. Tiotropium concentrations in plasma could
only be measured up to 2 hrs post dose in most of the studies in healthy
volunteers even with the adequate assay method (LC/MS/MS). This could be due to the high volume of
distribution and the small dose.
Therefore, PK parameters were estimated using the urine data. It should be noted that even urine data were
not optimally collected in most of studies (e.g., urine was collected usually
up to 4, 8, 24 hrs, not long enough compared to t1/2 of 5-6 days).
There is only one study (Study 205.105) that measured urine up to 25
days after tiotropium dose.
4.2.3. What are the characteristics of the
exposure-response relationships (dose-response, concentration-response) for
efficacy and safety?
The sponsor
conducted a dose-ranging study (Study 205.108) that was used to selct the dose
for Phase III program (see section 4.2.3.4, page 9).
4.2.3.1. Based on PK parameters, what is the degree
of linearity or non-linearity in the dose- concentration relationship?
Dose
proportionality was evaluated using the data after iv infusion, oral
administration and dry powder inhalation of tiotropium.
Intravenous doses: As shown in
Table 1, there was a trend to increased urinary excretion after doses of 2.4,
4.8, 9.6 and 14.4 ΅g tiotropium. A
similar trend was observed for plasma concentrations (Study 205.107).
Table 1. Geometric mean (% gCV): data from Study 205.107 after single iv infusion
|
Dose |
2.4 ΅g |
4.8 ΅g |
9.6 ΅g |
14.4 ΅g |
|
Ae0-24h (% of dose) |
39.3 (7) |
42.0 (17) |
46.0 (6) |
54.3 (4) |
|
C15min (pg/mL)a |
322.8 (9) |
375 (16) |
306 (24) |
390 (22) |
Oral doses: Tiotropium
plasma concentrations were regularly below the limit of quantification and are therefore
not discussed. Urinary excretion seemed
to increase slightly with higher doses; 0.72%, 0.84%, 0.69% and 0.99% of dose
were renally excreted over 24 hours for 8, 16, 32 and 64 ΅g respectively (Study
205.106).
Inhalation doses: The geometric mean urinary excretion data (Ae0-4h) after a single and multiple doses are summarized in
Table 2.
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Table 2. Geometric mean % of tiotropium dose excreted unchanged in urine in the interval 0-4 h after dry powder inhalation by young healthy subjects
Note: multiple
dose measured on Day 14 (Study 205.104) and 7 (Study 205.103)
As show in
Table 2, there is a trend to higher urinary excretion after the higher
doses. A similar trend was observed for
urinary excretion, such as, 10.5%, 12.1% and 14.7% of the dose were excreted
unchanged within 24 hours after doses of 8.8, 17.6 and 35.2 ΅g tiotropium
measured on Day 14, respectively (Study 205.104). The reason(s) for this trend is not known. The sponsor speculates that an easier
elimination could occur from the binding sites (including muscarinic receptors)
for the higher doses due to saturation of the binding sites. Dose proportionality within the therapeutic
range cannot be determined due to insufficient data.
4.2.3.2. Do PK
parameters change with time following chronic dosing?
No, the
second once daily tiotropium inhalation dose (at a low dose range) generates
consistently slightly higher AUC values than expected from the first dose (also
seen it after intravenous infusion in Study 205.107). The reason for this finding is not know, however the sponsor
suggested that this might be due to incomplete saturation of binding sites
(including muscarinic receptors) after the first dose and a very slow dissociation
constant of the tiotropium binding site complex. Once all binding sites are at least near to saturation, more
tiotropium can escape from the tissue and the drug appears faster in the
systemic circulation, which leads to higher systemic plasma
concentrations. Urinary excretion
indicated an accumulation by the factor 2-3 from first to the fourteenth
inhalation.
4.2.3.3. How long is the time to the onset and offset
of the pharmacological response or clinical endpoint?
See Figure 2
on page 10 for study that measure pharmacodynamic endpoint (FEV1).
4.2.3.4. Are the dose and dosing regimen consistent
with the known relationship between dose-concentration-response, and are there
any unresolved dosing or administration issues?
Dose-Response relationship (Efficacy): A dose ranging study with a four-week multiple dose
design (Study 205.108) showed that tiotropium administered once a day by oral
inhalation via the FO2 inhalation device over a range of doses (4.4, 8.8,
17.6 and 35.2 mg) was considered safe and effective. Emax model was fitted to the dose-response data (Figure
1). As shown in Figure 1, there is no
apparent relationship (may be trends) between dose and response (FEV1).
Nevertheless, this study and two other dose-ranging studies (Study
205.119 and Study 205.120) provided support for a selection of 18 mg dose of titropium for the phase III program.
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Figure 1. Emax Model of Dose-Response Data (205.108)
The
relationship between the pharmacokinetics of tiotropium and the efficacy or
safety variables was not explored in this submission. Safety parameters (see page 8 under 4.2.1 question) were measured
at various times throughout the trial.
2nd Peak in Time-Response data: Approximately 24 hrs after a single dose inhalation of tiotropium, response (measured by mean FEV1) was increased (2nd peak) in dose ranging studies (Figure 2). The 2nd peak was shown also in patients who received a placebo (smaller peak compared to the patients who received tiotropium). This 2nd peak could not be attributed to PK of tiotropium (no active metabolites, no enterohepatic recirculation) or to the intrinsic/extrinsic factors. It could be, as the sponsor suggested, due to the circadian rhythm.
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4.2.4. How does
the PK of tiotropium in healthy volunteers compared to that in patients
following dry powder inhalation? What
are the basic PK parameters? Is this a
high extraction ratio or a low extraction ratio drug?
Pharmacokinetics
after intravenous doses: Tiotropium
was infused in doses ranging from 2.4 to 14.4 ΅g over 15 minutes in healthy
male subjects (Studies 205.105, 107 and 134).
Tiotropium plasma concentrations at the end of the infusion (Cmax) reached dose-normalized (to 18 mg) values of 320-440 pg/mL for 14.4 ΅g depending on
the subject group tested. Study 205.105
provided the most complete pharmacokinetics of tiotropium among studies
conducted (in this study, tiotropium was administered also by inhalation as
well as orally): the mean (% gCV)
values of volume of distribution (Vss), total clearance, renal clearance, half-life and the
residence time of tiotropium after 14.4 ΅g iv dose are of 32 L/kg (27.8% gCV),
880 mL/min (22.1% gCV), 669 mL/min (16.5% gCV), 5.7 days (26% gCV) and 50.6 hrs
(31.5% gCV), respectively. Urinary
excretion as an unchanged tiotropium was 73.6% in young healthy subjects after
intravenous infusions and 14.4% after dry powder inhalation. Urinary excretion in the first 4 (or 24)
hours was already 43.8% (53.6%) of the dose (thus 59% and 72% of the total
urinary excretion are achieved within 4 hours and 24 hours). The long t1/2 was not explained by the binding of tioptropium to
erythrocytes, but expected due to binding of tioptropium to tissues.
Table 3. Geometric mean (% gCV) tiotropium PK parameters after intravenous infusion
of 14.4 ΅g, dry powder (DP) inhalation of 108 ΅g or oral solution of 64 ΅g
tiotropium to different groups of twelve healthy male subjects,
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Pharmacokinetics
after inhalation: Tiotropium
was rapidly absorbed after inhalation regardless the inhalation device used in
any studies. The earliest blood sample
was always scheduled 5 minutes after inhalation and this plasma sample
contained with a few exceptions always the highest tiotropium concentration (Cmax) of the complete profile, suggesting a very rapid
absorption. Then, tiotropium
concentrations fell rapidly afterwards in an polyexponential (the sponsor used
4-5 compartment model) manner and were usually not quantifiable after 2 to 8
hours post inhalation, while urinary excretion was quantifiable for days after
a single inhalation. Urinary excretion
rates declined polyexponentially until they reached an apparent terminal
elimination phase at about 96 hours post dose.
Urinary excretion after a single dose (Ae0-•) was 14.4% (7.8% gCV) for a dose of 108 ΅g in Study
205.105. This was the only study which
collected urine long enough for a reliable calculation. The terminal elimination half-life was 4.84
days in the Study 205.105 and geometric mean values ranged from 5 to 7 days in
other studies. The pharmacokinetic parameter values from Study 205.105 are
shown in Table 3.
PK parameters
from individual studies following a single and multiple doses of tiotropium by
inhalation in healthy subjects and patients with COPD or asthma are summarized
in Table 4.
|
Study |
Dose (mg) |
C5min (pg/mL) |
AUC0-2h (pg∑h/mL) |
Ae0-4h % of dose |
Ae0-24h % of dose |
CLr (mL/min) |
t1/2 (days) |
|
Single Dose |
|||||||
|
205.103 |
70.4 |
8.61 (63) |
6.4 (64) |
1.33 (54) |
- |
- |
- |
|
|
141 |
13.7 (75) |
9.4 (58) |
1.78 (62) |
- |
- |
- |
|
205.104 |
8.8 |
- |
- |
1.34 (35) |
3.30 (27) |
- |
- |
|
|
17.6 |
15.1 (94) |
- |
1.61 (65) |
4.64 (48) |
- |
- |
|
|
35.2 |
6.9 (32) |
- |
1.31 (50) |
3.70 (6) |
- |
- |
|
205.105 |
108 |
10.9 (58) |
6.65 (39) |
1.84 (41) |
4.99 (22) |
486 (14) |
4.8 (16) |
|
205.108 |
8.8 17.6 |
- 6.53 (44) |
- - |
- - |
- - |
- - |
- - |
|
|
35.2 |
10.07 (80) |
- |
- |
- |
- |
- |
|
205.120 |
8.8 |
- |
- |
0.85 (89) |
- |
- |
- |
|
|
17.6 |
- |
- |
1.50 (55) |
- |
- |
- |
|
|
35.2 |
7.52 (21) |
- |
1.70 (27) |
- |
- |
- |
|
|
70.4 |
8.57 (56) |
- |
1.69 (25) |
- |
- |
- |
|
205.133 |
18a |
4.87 (69) |
5.99 (28) |
0.61 (143) |
- |
- |
- |
|
|
18b |
7.06 (83) |
8.12 (46) |
0.66 (66) |
- |
- |
- |
|
205.201 |
18 36 |
- - |
- - |
0.53 (66)c 0.92 (105)c |
- - |
- - |
- - |
|
Multiple Dose |
|||||||
|
205.103 |
70.4 |
16.4 (49) |
|
|
|
|
|
|
|
141 |
25.4 (57) |
|
|
|
|
|
|
205.104 |
8.8 |
16.2 (50) |
- |
3.13 (50) |
10.5 (26) |
|
5.8 (23) |
|
|
17.6 |
25.1 (58) |
- |
3.63 (39) |
12.1 (20) |
|
7.7 (31) |
|
|
35.2 |
16.5 (16) |
16.4 (7) |
4.28 (25) |
14.7 (14) |
407 (8) |
6.0 (21) |
|
205.108 |
8.8 |
13.5 (39)d |
|
|
4.8 (28)d |
|
|
|
|
17.6 |
7.68 (36) d |
|
|
3.97 (48)d |
|
|
|
|
35.2 |
18.31(35)d |
|
|
4.75 (38)d |
|
|
|
205.117 |
18 |
15.3 (63)e 19.2 (73)f 16.1 (72)g 19.0 (45)h |
- |
2.02 (52)c 1.46 (82)c 1.32 (54)c 0.98 (77)c |
6.63 (66) 7.01 (38) 6.95 (45) 7.43 (59) |
- |
- |
|
205.133 |
18a 18b |
9.63 (142) 15.3 (60) |
10.8 (84) 15.7 (67) |
1.97 (74) 1.42 (89) |
- - |
326 (60) 163 (93) |
5.5 (29) 6.5 (29) |
|
205.201 |
18 36 |
- - |
- - |
1.19 (122)c 2.15 (61)c |
- - |
- - |
- - |
Urinary
excretion of tiotropium were 1.61% of dose (64.8% gCV) in the interval 0-4 h
and 4.64% (47.6% gCV) in the fraction 0-24 h in Study 205.104, while those
values in Study 205.105 were 1.84% (40.7% gCV) and 4.99% (22.4% gCV),
respectively. In COPD patients, urinary
excretion of tiotropium showed lower values with 0.61-0.66% in the 4 h interval
(Study 205.133).
A comparison
of Ae0-4h (1.84%) and Ae0-24h (4.99%) values with the total urinary excretion
(14.4%) in Study 205.105 showed a different behavior in contrast to the
excretion after an intravenous dose.
About 12.8% (= 1.84/0.144) and 34.7% (= 4.99/0.144) of the total
excretion was complete 4 and 24 hours after inhalation. This is much less than for infusion with
59.5% and 72.8% for the same time intervals.
There was therefore a clear difference in tiotropium disposition between
intravenous infusion and inhalation.
The reason is not known, however, as the sponsor suggested, this could
be due to a more pronounced tissue binding sites in the lung after inhalation. The fraction of an intravenous infusion,
which gets access to lung tissue is smaller and the load for the kidney becomes
much higher, which results in a faster excretion. The longer mean residence time of 110 h (18.2% gCV) after
inhalation vs 50.6 hours (31.5% gCV)
after infusion fits in this view.
Multiple doses:
Pharmacokinetic profiles after 7 (Study 205.103 and 133) or 14 days
(Study 205.104 and 133) were investigated in Phase I studies. Urinary excretion in asthma patients was also
studied after 21 days in Study 205.201.
The following results are summarized based on these studies:
∑ The accumulation factor did not exceed the 2-3 despite
a terminal elimination half-life of 5-7 days and a once daily dosing
regimen. This suggests that long
terminal elimination half-life is not dominant (Study 205.103). It was shown that there was no further
accumulation with continued tiotropium inhalation (e.g. over weeks and
months). Peak as well as trough plasma
concentrations and urinary excretion remained approximately constant over
months once a steady state was achieved (Study 205.117).
∑ Based on t1/2 of 5-7 days, steady state conditions are expected to
be reached 3-5 weeks of continued treatment and such a long treatment time was
only reached in the 4-week Study 205.108 and the 1-year safety and efficacy
studies (Study 205.114/117). However,
the scatter in the data does often not allow differentiating between data after
7 and 14 days treatment. Thus
approximate steady state conditions is achieved after 7-14 days treatment.
∑ Geometric mean tiotropium concentrations in healthy
subjects 5 minutes after a 17.6 ΅g tiotropium dose given for 14-days inhalation
were 24.6 pg/mL (58% gCV) after a 17.6 ΅g tiotropium dose given for 14-days
(Study 205.104). Corresponding values
in COPD patients were 9.63 pg/mL (142% gCV) and 15.3 pg/mL (60.0% gCV) in
younger (mean 53 years of age) and older patients (mean 74 years of age),
respectively (Study 205.133). In COPD
patients (Study 205.117), C5min and C-5min (trough) at true steady state conditions (e.g.,
measurements on Day 50 or 92) were about 18.6 and 5.8 pg/mL, respectively. 24-h urine samples at steady state
conditions (Day 50) showed 7.01% of dose (62.6% gCV) for female and 7.12% of
dose (38.2% gCV) for male patients were excreted in urine (Study 205.117). Therefore, this data suggests that steady
state conditions are not much different from the status achieved within 2 weeks
of treatment.
∑ Urinary excretion of tiotropium in healthy subjects
reached 3.63% of dose (39.1% gCV) in the interval 0-4 h after two weeks and
12.1% of dose in the interval 0-24 h (Study 205.104). Corresponding values in COPD patients for the interval 0-4 h were
1.42% (88.7% gCV) to 1.97% (74.4% gCV) in older and younger patients of Study
205.133, respectively.
Absolute bioavailability: Absolute
bioavailability was 19.5% after an inhalation (Study 205.105). The respective value for an oral dose is
between 2% and 3%. This means that
about 17% of the inhaled dose reached the lung, while up to 83% were swallowed
(assume full bioavailability from the lung).
Overall
summary: Tiotropium
is a quaternary amine and it is not readily absorbed into the systemic
circulation. This was confirmed by the
low bioavailability of 2-3% for oral solutions in young healthy subjects, while
tiotropium showed an absolute bioavailability of 19.5% in these subjects. Urinary excretion of unchanged drug was
73.6% and 14.4% (Ae0-•) of the dose after an intravenous and inhalation dose
respectively in healthy subjects and 7% (Ae0-24h) after inhalation of tiotropium in COPD
patients. The drug has a high volume of
distribution of 32 L/kg, a total clearance of 880 mL/min and a terminal
elimination half-life of 5-6 days. The
renal clearance of tiotropium (669 mL/min after an iv dose) exceeds the
creatinine clearance, which suggests the presence of active secretion into
kidney tubules. After multiple
administration, (approximate) steady state was reached after 2-3 weeks with an
accumulation factor of about two to three.
Pharmacokinetics linearity of tiotropium could not be confirmed due to
insufficient data.
Plasma
concentrations (e.g., C5min, AUC) and urinary excretion of tiotropium in urine
were lower in patients with COPD or asthma compared those in healthy subjects
(Table 3). Absorption of the drug could
be affected by the Disease State (COPD/asthma), however, it is not exactly
known, because this effect is hard to separate from the confounding effects of
age on the urinary excretion.
4.2.5. Does
mass balance suggest renal or hepatic the major route of elimination?
A mass
balance study of tiotropium in humans was not conducted. The sponsor stated that this was not
possible due to the combination of analytical problems and the PK
characteristics of tiotropium (i.e., large Vss, long t1/2, metabolism play a minor role in the excretion of
tiotropium, inhalation route of administration, etc.). However, following iv infusion 73.6% of the
dose is excreted in urine as unchanged drug.
The remaining 25% of the dose undergo nonenzymatic hydrolysis and CYP
450 metabolism (see section 4.4.2, page 17).
4.3 Intrinsic Factors
4.3.1 What are the relevant covariates that
influence the pharmacokinetic variability of tiotropium?
Pharmacokinetics in elderly subjects with COPD: Study
205.133 evaluated age factor on PK of tiotropium in patients with COPD, and the
results are summarized in Table 5.
Renal clearance of tiotropium was significantly lower in the elderly
patients (163 mL/min) compared with younger patients (326 mL/min). C5min and AUC0-4h were 59% and 43% higher, respectively, in the elderly
than the younger COPD patients (Day 14).
However, age factor on the PK of tiotropium can not be confirmed due to
the confounding factor of old age (compromised renal function). Table 6 lists multiple dose pharmacokinetic
parameters in subjects of various age groups.
Table 5. Geometric mean PK parameters in elderly (69-80 yrs) and young (45-58 yrs) patients
|
|
Note: (1) Elderly = mean age of 74 years (range 69-80
years); Young = mean age of 53
years (range 45-58 years). (2) Drug plasma concnetrations below 5 pg/mL
(LOQ) were
replaced by _ the LOQ to
calculate PK parameters. Parameter
values with a high incidence
of replaced values were set
into brackets.
|
|
Table.
Multiple dose tiotropium pharmacokinetic parameters (geometric means)
for dry powder inhalation and different age groups
Pharmacokinetics
in subjects with renal impairment: PK of
tiotropium was compared in four different groups of subjects with normal to
severe renal impairment following an intravenous dose of 4.8 ΅g (Study
205.134). The results are summarized in
Table 7.
The effect of
a renal insufficiency on tiotropium plasma concentrations after inhalation was
also evaluated in Study 205.117 (COPD patients). Trough tiotropium plasma concentrations (C-5min) at steady state (Day 92) increased by about 10% and
27% in mild and moderate impairment, respectively, compared to patients with
normal renal function. C5min,ss (Day 92) increased by 90% and 188% in mild and moderate
impairment, respectively, compared to patients with normal renal function. Increase in tiotropium plasma concentrations
was associated with a decrease of Ae0-24h, ss 0.3% and 33% in mild and moderate renal impairment,
respectively, compared to patients with normal renal function. Therefore tiotropium should be used with
caution in patients with renal impairment, especially those with moderate and
severe impairment.
|
|
Table 7. Geometric mean (% gCV) tiotropium pharmacokinetic parameters after intravenous infusion of 4.8 ΅g tiotropium to subjects with varying degrees of renal impairment.
Pharmacokinetics
in subjects with hepatic impairment: No study was
performed in patients with hepatic impairment.
Tiotropium was predominantly cleared by renal elimination as a parent
drug (~70% of the dose is excreted in urine in healthy young subjects),
therefore, approximately 30% of dose are expected to be eliminated as
metabolites. Tiotropium was degraded by
nonenzymatic ester cleavage (U98-2865).
Also, tiotropium was metabolized by CYP 2D6 and probably by CYP
3A4. Therefore, there is possible
interaction with drug(s) that are substrate of CYP 2D6 and 3A4, such as
quinidine and ketoconazole, and concern for CYP 2D6 poor metabolizers. Four subjects from the study 205.222 were
identified (by genotype). AUC0-4h was 33% higher in the poor 2D6 metabolizers in
comparison to the extensive 2D6 metabolizers.
However,
overall, based on the low extent of overall metabolism of the drug (<30%)
and low tiotropium plasma concentrations (0.01 and 0.05 nmol/L) after 18 ΅g dry
powder inhalation dose, a clinically significant change due to metabolic
interaction or hepatic dysfunction is not anticipated. Similarly, PK change shown in poor 2D6
metabolizers does not warrant the lower dosing regimen.
Pharmacokinetics
in subjects of different human races: Urinary
excretion data in Study 205.201 indicated no clinically significant difference
between Caucasian and African-American COPD patients. However, the majority of patients were Caucasians (95 Caucasians vs 9 African-Americans), therefore, the
ethnicity factor is not conclusively confirmed.
PK in
Pediatric patients:
Pharmacokinetic data in subjects under an age of 18 years are not
available. Tiotropium inhalation powder
was intended for the maintenance treatment of bronchospasm and dyspnea
associated with COPD including chronic bronchitis and emphysema. Since the
disease being treated is typically found in older patients, the lack of data in
subjects with an age of less than 18 years is not considered to be an issue.
4.4 Extrinsic Factors
4.4.1. What are the extrinsic factors (drugs, herbal
products, diet, smoking, and alcohol) influence exposure and/or response of
tiotropium?
The influence
of above mentioned extrinsic factors on the PK and/or PD were not evaluated.
4.4.2. Is there an in vitro basis to suspect in
vivo drug-drug interactions?
Some of the
administered dose (<30%) of tiotropium is metabolized by cytochrome CYP 2D6
and probably CYP 3A4. Therefore, there
may be potential interactions with inhibitors of these two enzymes (e.g.,
quinidine, gestodene, ketoconazole). No
clinical studies have been performed to evaluate the interactions. However, based on the low extent of overall
metabolism of the drug (<30%) and low tiotropium plasma concentrations
(between 0.01 and 0.05 nmol/L) after a dose of 18 ΅g by dry powder inhalation,
clinically significant metabolic interaction is not anticipated.
Since mass
balance study in human was not conducted, metabolism was investigated using in vitro studies (and in vivo animal studies). In
vitro metabolism of tiotropium was investigated in human liver microsomes
and in liver microsomes from mice, rats, and dogs to compare the metabolic
pattern between species (U99-1348). The
results from this study are summarized as follows:
∑ Ba 679 BR is metabolized by CYP resulting in the
formation of N-methylscopine. The site
of metabolic attack was the dithienylglycolie acid moiety.
∑ The metabolic pathways leading to the metabolites
observed in vitro are oxidation in
the thiophene ring systems, glutathione conjugation and oxidative cleavage of
thiophene ring systems.
∑ Enzymatic cleavage of the ester linkage either by
esterases or by CYP does not occur.
∑ Use of enzyme specific chemical inhibitors (e.g.,
ketoconazole, quinidine), recombinant CYPs, and correlation analysis showed the
involvement of CYP 3A4 (minor) and CYP 2D6 (dominant) the metabolism of Ba 679
BR.
∑ These principal pathways were also observed with rat
and human hepatocytes.
∑ Metabolism is marginal in rat lung microsomes compared
to rat liver microsomes.
Stability of tiotropium bromide in plasma was evaluated in vitro. Tiotropium bromide is stable in acidic aqueous solutions (pH
2). The hydrolytic cleavage becomes
more rapid with increasing pH and had a hydrolysis half-life of 17 h at 37 °C
in pH 7.4 plasma as well as in 0.1 M phosphate buffer pH 7.25 (U91-0236). The hydrolysis of the ester bond was
temperature-sensitive, as the rate of hydrolysis was threefold lower at 25°C
(U91-0236).
The possible involvement of esterases as well as the possible species
specificity of tiotropium cleavage in plasma was investigated in EDTA-plasma of
mice, rats, dogs, rabbits and humans (U98-2865). Neither physostigmine, paraoxon, PMSF nor PCMB (esterase
inhibitors) influenced the hydrolysis of tiotropium bromide. BEA 2108 BR, a structurally related compound
to tiotropium bromide, had also no effect on tiotropium bromide hydrolysis. The results indicated that plasma esterase
enzymes did not contribute to the hydrolysis of tiotropium bromide. This study showed that hydrolytic cleavage
of the ester bond of tiotropium (formed to N-methylscopine and
dithienylglycolic acid) was occurred in plasma, therefore, it occurred via
nonenzymatic reaction. Inhibition of
CYPP450 by tiotropium was investigated (U97-2651). The results showed that tiotropium (used concentrations of 1
΅mol/L) did not inhibit cytochrome P 450 1A1, 1A2, 2B1, 2C9, 2C19, 2D6, 2E1, or
3A4 in human liver microsomes.
In summary,
metabolism plays a minor role in the elimination of the drug from the body
(73.6% renal excretion of unchanged drug after an iv dose). It showed that hydrolytic cleavage of the
ester bond of tiotropium occurred in plasma (formed to N-methylscopine and
dithienylglycolic acid). A (minor)
amounts are metabolized by the cytochrome CYP 450 2D6 and probably CYP 450 3A4
involving the formation of N-methylscopine and a variety of glutathione conjugates
after oxidation of the thiophen ring system.
4.4.3. Is the drug an inhibitor and/or an inducer of
CYP enzymes?
In vitro study showed that
high tiotropium concentrations of 1 ΅mol/L did not inhibit cytochrome P 450
1A1, 1A2, 2B1, 2C9, 2C19, 2D6, 2E1, or 3A4 (U97-2651) in human liver microsomes.
4.4.4. Are there other metabolic/transporter
pathways that may be important?
Interactions via p-glycoprotein