Mechanism Of Action
Lubiprostone is a locally acting chloride channel
activator that enhances a chloride-rich intestinal fluid secretion without
altering sodium and potassium concentrations in the serum. Lubiprostone acts by
specifically activating ClC-2, which is a normal constituent of the apical
membrane of the human intestine, in a protein kinase A–independent fashion.
By increasing intestinal fluid secretion, lubiprostone
increases motility in the intestine, thereby facilitating the passage of stool
and alleviating symptoms associated with chronic idiopathic constipation. Patch
clamp cell studies in human cell lines have indicated that the majority of the
beneficial biological activity of lubiprostone and its metabolites is observed
only on the apical (luminal) portion of the gastrointestinal epithelium.
Lubiprostone, via activation of apical ClC-2 channels in
intestinal epithelial cells, bypasses the antisecretory action of opiates that
results from suppression of secretomotor neuron excitability.
Activation of ClC-2 by lubiprostone has also been shown
to stimulate recovery of mucosal barrier function and reduce intestinal
permeability via the restoration of tight junction protein complexes in ex vivo
studies of ischemic porcine intestine.
Although the pharmacologic effects of lubiprostone in
humans have not been fully evaluated, animal studies have shown that oral
administration of lubiprostone increases chloride ion transport into the
intestinal lumen, enhances fluid secretion into the bowels, and improves fecal
Following oral administration, concentrations of
lubiprostone in plasma are below the level of quantitation (10 pg/mL).
Therefore, standard pharmacokinetic parameters such as area under the curve
(AUC), maximum concentration (Cmax), and half-life (t½) cannot be reliably
calculated. However, the pharmacokinetic parameters of M3 (only measurable
active metabolite of lubiprostone) have been characterized.
Peak plasma concentrations of M3, after a single oral
dose of 24 mcg of lubiprostone, occurred at approximately 1.1 hours. The Cmax was
41.5 pg/mL and the mean AUC0–t was 57.1 pg·hr/mL. The AUC0–t of M3 increases
dose proportionally after single 24-mcg and 144-mcg doses of lubiprostone
(6-times the maximum recommended 24 mcg dose).
A study was conducted with a single 72-mcg dose of 3H-labeled
lubiprostone (3-times the maximum recommended 24 mcg dose) to evaluate the
potential of a food effect on lubiprostone absorption, metabolism, and
excretion. Pharmacokinetic parameters of total radioactivity demonstrated that
Cmax decreased by 55% while AUC0–∞ was unchanged when lubiprostone was
administered with a high-fat meal. The clinical relevance of the effect of food
on the pharmacokinetics of lubiprostone is not clear. However, lubiprostone was
administered with food and water in a majority of clinical trials.
In vitro protein binding studies indicate lubiprostone is
approximately 94% bound to human plasma proteins.
Lubiprostone is rapidly and extensively metabolized by
15-position reduction, α-chain βoxidation, and ω-chain
ω-oxidation. In vitro studies using human liver microsomes indicate that
cytochrome P450 isoenzymes are not involved in the metabolism of lubiprostone.
Further in vitro studies indicate that M3, a metabolite of lubiprostone, is
formed by the reduction of the 15carbonyl moiety to a hydroxy moiety by
microsomal carbonyl reductase. M3 makes up less than 10% of the dose of
Animal studies have shown that metabolism of lubiprostone
rapidly occurs within the stomach and jejunum, most likely in the absence of
any systemic absorption.
Lubiprostone could not be detected in plasma; however, M3
has a t½ ranging from 0.9 to 1.4 hours. After a single oral dose of 72 mcg of 3H-labeled
lubiprostone, 60% of total administered radioactivity was recovered in the
urine within 24 hours and 30% of total administered radioactivity was recovered
in the feces by 168 hours. Lubiprostone and M3 are only detected in trace
amounts in human feces.
Male And Female Patients
The pharmacokinetics of M3 were similar between male and
Patients With Renal Impairment
Sixteen subjects, 34 to 47 years old (8 severe renally
impaired subjects [creatinine clearance (CrCl) less than 20 mL/min] who
required hemodialysis and 8 control subjects with normal renal function [CrCl
above 80 mL/min]), received a single oral 24-mcg dose of Amitiza. Following
administration, lubiprostone plasma concentrations were below the limit of
quantitation (10 pg/mL). Plasma concentrations of M3 were within the range of
exposure from previous clinical experience with Amitiza.
Patients With Hepatic Impairment
Twenty-five subjects, 38 to 78 years old (9 with severe
hepatic impairment [Child-Pugh Class C], 8 with moderate impairment [Child-Pugh
Class B], and 8 with normal liver function), received either 12 mcg or 24 mcg
of Amitiza under fasting conditions. Following administration, lubiprostone
plasma concentrations were below the limit of quantitation (10 pg/mL) except
for two subjects. In moderately and severely impaired subjects, the Cmax and
AUC0–t of the active lubiprostone metabolite M3 were increased, as shown in
Table 6: Pharmacokinetic Parameters of the Metabolite
M3 for Subjects with Normal or Impaired Liver Function following Dosing with
|Liver Function Status
||Mean (SD) AUCo-(pg•hr/mL)
||% Change vs. Normal
||Mean (SD) Cmax (pg/mL)
||% Change vs. Normal
|Child-Pugh Class B (n=8)
|Child-Pugh Class C (n=8)
These results demonstrate that there is a correlation
between increased exposure of M3 and severity of hepatic impairment. [see Use
In Specific Populations]
Drug Interaction Studies
Based upon the results of in vitro human microsome
studies, there is low likelihood of pharmacokinetic drug–drug interactions with
lubiprostone. Additionally, in vitro studies in human liver microsomes
demonstrate that lubiprostone does not inhibit cytochrome P450 isoforms 3A4,
2D6, 1A2, 2A6, 2B6, 2C9, 2C19, or 2E1, and in vitro studies of primary cultures
of human hepatocytes show no induction of cytochrome P450 isoforms 1A2, 2B6,
2C9, and 3A4 by lubiprostone. Based on the available information, no protein
binding–mediated drug interactions of clinical significance are anticipated.
Chronic Idiopathic Constipation In Adults
Two double-blinded, placebo-controlled studies of
identical design were conducted in patients with CIC. CIC was defined as, on
average, less than 3 SBMs per week (a SBM is a bowel movement occurring in the
absence of laxative use) along with one or more of the following symptoms of
constipation for at least 6 months prior to randomization: 1) very hard stools
for at least a quarter of all bowel movements; 2) sensation of incomplete
evacuation following at least a quarter of all bowel movements; and 3)
straining with defecation at least a quarter of the time.
Following a 2-week baseline/washout period, a total of
479 patients (mean age 47 [range 20 to 81] years; 89% female; 81% Caucasian,
10% African American, 7% Hispanic, 2% Asian, 11% at least 65 years of age) were
randomized and received Amitiza 24 mcg twice daily or placebo twice daily for 4
weeks. The primary endpoint of the studies was SBM frequency. The studies
demonstrated that patients treated with Amitiza had a higher frequency of SBMs
during Week 1 than the placebo patients. In both studies, results similar to
those in Week 1 were also observed in Weeks 2, 3, and 4 of therapy (Table 7).
Table 7: Adult Spontaneous Bowel Movement Frequency
Rates1 (Efficacy Studies)
||Baseline Mean± SD Median
||Week 1 Mean ± SD Median
||Week 2 Mean ± SD Median
||Week 3 Mean ± SD Median
||Week 4 Mean ± SD Median
||Week 1 Change from Baseline Mean ± SD Median
||Week 4 Change from Baseline Mean ± SD Median
||1.6 ± 1.3
||3.5 ± 2.3
||3.2 ± 2.5
||2.8 ± 2.2
||2.9 ± 2.4
||1.9 ± 2.2
||1.3 ± 2.5
|Amitiza 24 mcg Twice Daily
||1.4 ± 0.8
||5.7 ± 4.4
||5.1 ± 4.1
||5.3 ± 4.9
||5.3 ± 4.7
||4.3 ± 4.3
||3.9 ± 4.6
||1.5 ± 0.8
||4.0 ± 2.7
||3.6 ± 2.7
||3.4 ± 2.8
||3.5 ± 2.9
||2.5 ± 2.6
||1.9 ± 2.7
|Amitiza 24 mcg Twice Daily
||1.3 ± 0.9
||5.9 ± 4.0
||5.0 ± 4.2
||5.6 ± 4.6
||5.4 ± 4.8
||4.6 ± 4.1
||4.1 ± 4.8
|1Frequency rates are calculated as 7 times
(number of SBMs) / (number of days observed for that week).
In both studies, Amitiza demonstrated increases in the
percentage of patients who experienced SBMs within the first 24 hours after
administration when compared to placebo (57% vs. 37% in Study 1 and 63% vs. 32%
in Study 2, respectively). Similarly, the time to first SBM was shorter for
patients receiving Amitiza than for those receiving placebo.
Signs and symptoms related to constipation, including
abdominal bloating, abdominal discomfort, stool consistency, and straining, as
well as constipation severity ratings, were also improved with Amitiza versus
placebo. The results were consistent in subpopulation analyses for gender,
race, and elderly patients at least 65 years of age).
During a 7-week randomized withdrawal study, patients who
received Amitiza during a 4-week treatment period were then randomized to
receive either placebo or to continue treatment with Amitiza. In
Amitiza-treated patients randomized to placebo, SBM frequency rates returned
toward baseline within 1 week and did not result in worsening compared to
baseline. Patients who continued on Amitiza maintained their response to therapy
over the additional 3 weeks of treatment.
Opioid-Induced Constipation In Adults With Chronic
The efficacy of Amitiza in the treatment of OIC in
patients receiving opioid therapy for chronic, non-cancer-related pain was
assessed in three randomized, double-blinded, placebo-controlled studies. In
Study 1, the median age was 52 years (range 20 to 82) and 63% were female. In
Study 2, the median age was 50 years (range 21 to 77) and 64% were female. In
Study 3, the median age was 50 years (range 21 to 89) and 60% were female.
Patients had been receiving stable opioid therapy for at least 30 days prior to
screening, which was to continue throughout the 12-week treatment period. At
baseline, mean oral morphine equivalent daily doses (MEDDs) were 99 mg and 130
mg for placebo-treated and Amitiza-treated patients, respectively, in Study 1.
Baseline mean MEDDs were 237 mg and 265 mg for placebo-treated and
Amitiza-treated patients, respectively, in Study 2. In Study 3, baseline mean
MEDDs were 330 mg and 373 mg for placebo-treated and Amitiza-treated patients,
respectively. The Brief Pain Inventory-Short Form (BPI-SF) questionnaire was
administered to patients at baseline and monthly during the treatment period to
assess pain control. Patients had documented opioid-induced constipation at
baseline, defined as having less than 3 spontaneous bowel movements (SBMs) per
week, with at least 25% of SBMs associated with one or more of the following
conditions: (1) hard to very hard stool consistency; (2) moderate to very
severe straining; and/or (3) having a sensation of incomplete evacuation.
Laxative use was discontinued at the beginning of the screening period and
throughout the study. With the exception of the 48-hour period prior to first
dose and for at least 72 hours (Study 1) or 1 week (Study 2 and Study 3)
following first dose, use of rescue medication was allowed in cases where no
bowel movement had occurred in a 3-day period. Median weekly SBM frequencies at
baseline were 1.5 for placebo patients and 1.0 for Amitiza patients in Study 1
and, for both Study 2 and Study 3, median weekly SBM frequencies at baseline
were 1.5 for both treatment groups.
In Study 1, patients receiving non-diphenylheptane (e.g.,
non-methadone) opioids (n = 431) were randomized to receive placebo (n = 217)
or Amitiza 24 mcg twice daily (n = 214) for 12 weeks.
The primary efficacy analysis was a comparison of the
proportion of “overall responders” in each treatment arm. A patient was
considered an “overall responder” if ≥1 SBM improvement over baseline
were reported for all treatment weeks for which data were available and ≥3
SBMs/week were reported for at least 9 of 12 treatment weeks. The proportion of
patients in Study 1 qualifying as an “overall responder” was 27.1% in the group
receiving Amitiza 24 mcg twice daily compared to 18.9% of patients receiving
placebo twice daily (treatment difference = 8.2%; p-value = 0.03). Examination
of gender and race subgroups did not identify differences in response to
Amitiza among these subgroups. There were too few elderly patients (≥ 65
years of age) to adequately assess differences in effects in that population.
In Study 2, patients receiving opioids (N = 418) were
randomized to receive placebo (n = 208) or Amitiza 24 mcg twice daily (n = 210)
for 12 weeks. Study 2 did not exclude patients receiving diphenylheptane
opioids (e.g., methadone). The primary efficacy endpoint was the mean change
from baseline in SBM frequency at Week 8; 3.3 vs. 2.4 for Amitiza and
placebo-treated patients, respectively; treatment difference = 0.9; p-value =
0.004. The proportion of patients in Study 2 qualifying as an “overall
responder,” as prespecified in Study 1, was 24% in the group receiving Amitiza
compared to 15% of patients receiving placebo. In the subgroup of patients in
Study 2 taking diphenylheptane opioids (baseline mean [median] MEDDs of 691
 mg and 672  mg for placebo and Amitiza patients, respectively), the
proportion of patients qualifying as an “overall responder” was 20.5% (8/39) in
the group receiving Amitiza compared to 6.3% (2/32) of patients receiving
placebo. Examination of gender and race subgroups did not identify differences
in response to Amitiza among these subgroups. There were too few elderly
patients (≥ 65 years of age) to adequately assess differences in effects
in that population.
In Study 3, patients receiving opioids (N = 451) were
randomized to placebo (n = 216) or Amitiza 24 mcg twice daily (n = 235) for 12
weeks. Study 3 did not exclude patients receiving diphenylheptane opioids
(e.g., methadone). The primary efficacy endpoint was the change from baseline
in SBM frequency at Week 8. The study did not demonstrate a statistically
significant improvement in SBM frequency rates at Week 8 (mean change from
baseline of 2.7 vs. 2.5 for Amitiza and placebo-treated patients, respectively;
treatment difference = 0.2; p-value = 0.76).
The proportion of patients in Study 3 qualifying as an
“overall responder,” as prespecified in Study 1, was 15% in the patients
receiving Amitiza compared to 13% of patients receiving placebo. In the
subgroup of patients in Study 3 taking diphenylheptane opioids (baseline mean
[median] MEDDs of 730  mg and 992  mg for placebo and Amitiza
patients, respectively), the proportion of patients qualifying as an “overall
responder” was 2% (1/47) in the group receiving Amitiza compared to 12% (5/41)
of patients receiving placebo.
Irritable Bowel Syndrome With Constipation In Adults
Two double-blinded, placebo-controlled studies of similar
design were conducted in adult patients with IBS-C. IBS was defined as
abdominal pain or discomfort occurring over at least 6 months with two or more
of the following: 1) relieved with defecation; 2) onset associated with a
change in stool frequency; and 3) onset associated with a change in stool form.
Patients were sub-typed as having IBS-C if they also experienced two of three
of the following: 1) <3 spontaneous bowel movements (SBMs) per week, 2)
>25% hard stools, and 3) >25% SBMs associated with straining.
Following a 4-week baseline/washout period, a total of
1154 patients (mean age 47 [range 18 to 85] years; 92% female; 77% Caucasian,
13% African American, 9% Hispanic, 0.4% Asian; 8% at least 65 years of age)
were randomized and received Amitiza 8 mcg twice daily (16 mcg/day) or placebo
twice daily for 12 weeks. The primary efficacy endpoint was assessed weekly
utilizing the patient's response to a global symptom relief question based on a
7-point, balanced scale (“significantly worse” to “significantly relieved”):
“How would you rate your relief of IBS symptoms (abdominal discomfort/pain,
bowel habits, and other IBS symptoms) over the past week Â compared to how you
felt before you entered the study?”
The primary efficacy analysis was a comparison of the
proportion of “overall responders” in each arm. A patient was considered an
“overall responder” if the criteria for being designated a “monthly responder”
were met in at least 2 of the 3 months on study. A “monthly responder” was
defined as a patient who had reported “significantly relieved” for at least 2
weeks of the month or at least “moderately relieved” in all 4 weeks of that
month. During each monthly evaluation period, patients reporting “moderately
worse” or “significantly worse” relief, an increase in rescue medication use,
or those who discontinued due to lack of efficacy, were deemed non-responders.
The percentage of patients in Study 1 qualifying as an
“overall responder” was 14% in the group receiving Amitiza 8 mcg twice daily
compared to 8% of patients receiving placebo twice daily. In Study 2, 12% of
patients in the Amitiza 8 mcg group were “overall responders” versus 6% of
patients in the placebo group. In both studies, the treatment differences
between the placebo and Amitiza groups were statistically significant.
Results In Men
The two randomized, placebo-controlled, double-blinded
studies comprised 97 (8%) male patients, which is insufficient to determine
whether men with IBS-C respond differently to Amitiza from women.
During a 4-week randomized withdrawal period following
Study 1, patients who received Amitiza during the 12-week treatment period were
re-randomized to receive either placebo or to continue treatment with Amitiza.
In Amitiza-treated patients who were “overall responders” during Study 1 and
who were re-randomized to placebo, SBM frequency rates did not result in
worsening compared to baseline.