Lubiprostone 24 ug Capsule, Gelatin Coated, 60-count — NDC 0480-4138-06 (Billing 00480-4138-06)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics 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 transit.

12.3Pharmacokinetics 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 (C max ), and half-life (t ½ ) cannot be reliably calculated. However, the pharmacokinetic parameters of M3 (only measurable active metabolite of lubiprostone) have been characterized.

Absorption Peak plasma concentrations of M3, after a single oral dose of 24 mcg of lubiprostone, occurred at approximately 1.1 hours. The C max was 41.5 pg/mL and the mean AUC 0–t was 57.1 pg•hr/mL. The AUC 0–t of M3 increases dose proportionally after single 24-mcg and 144-mcg doses of lubiprostone (6-times the maximum recommended 24 mcg dose).

Food Effect A study was conducted with a single 72-mcg dose of 3 H-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 C max decreased by 55% while AUC 0–∞ 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. Distribution In vitro protein binding studies indicate lubiprostone is approximately 94% bound to human plasma proteins. Elimination Metabolism Lubiprostone is rapidly and extensively metabolized by 15-position reduction, α-chain β-oxidation, 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 15-carbonyl moiety to a hydroxy moiety by microsomal carbonyl reductase. M3 makes up less than 10% of the dose of radiolabeled lubiprostone.

Animal studies have shown that metabolism of lubiprostone rapidly occurs within the stomach and jejunum, most likely in the absence of any systemic absorption. Excretion Lubiprostone could not be detected in plasma; however, M3 has a t ½ ranging from 0.9 to 1.4 hours. After a single oral dose of 72 mcg of 3 H-labeled lubiprostone, 60% of total administered… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics 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 (C max ), and half-life (t ½ ) cannot be reliably calculated. However, the pharmacokinetic parameters of M3 (only measurable active metabolite of lubiprostone) have been characterized.

Absorption Peak plasma concentrations of M3, after a single oral dose of 24 mcg of lubiprostone, occurred at approximately 1.1 hours. The C max was 41.5 pg/mL and the mean AUC 0–t was 57.1 pg•hr/mL. The AUC 0–t of M3 increases dose proportionally after single 24-mcg and 144-mcg doses of lubiprostone (6-times the maximum recommended 24 mcg dose).

Food Effect A study was conducted with a single 72-mcg dose of 3 H-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 C max decreased by 55% while AUC 0–∞ 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. Distribution In vitro protein binding studies indicate lubiprostone is approximately 94% bound to human plasma proteins. Elimination Metabolism Lubiprostone is rapidly and extensively metabolized by 15-position reduction, α-chain β-oxidation, 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 15-carbonyl moiety to a hydroxy moiety by microsomal carbonyl reductase. M3 makes up less than 10% of the dose of radiolabeled lubiprostone.

Animal studies have shown that metabolism of lubiprostone rapidly occurs within the stomach and jejunum, most likely in the absence of any systemic absorption. Excretion Lubiprostone could not be detected in plasma; however, M3 has a t ½ ranging from 0.9 to 1.4 hours. After a single oral dose of 72 mcg of 3 H-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. Specific Populations Male and Female Patients The pharmacokinetics of M3 were similar between male and female subjects. 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 lubiprostone.

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 lubiprostone. 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 lubiprostone 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 C max and AUC 0–t of the active lubiprostone metabolite M3 were increased, as shown in Table 5. Table 5.

Pharmacokinetic Parameters of the Metabolite M3 for Subjects with Normal or Impaired Liver Function following Dosing with Lubiprostone Liver Function Status Mean (… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics 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 transit.

14 CLINICAL STUDIES

14.1Chronic 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 lubiprostone 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 lubiprostone 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 6). Table 6. Adult Spontaneous Bowel Movement Frequency Rates 1 (Efficacy Studies) Trial Study Arm 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 Study 1 Placebo 1.6 ± 1.3 1.5 3.5 ± 2.3 3.0 3.2 ± 2.5 3.0 2.8 ± 2.2 2.0 2.9 ± 2.4 2.3 1.9 ± 2.2 1.5 1.3 ± 2.5

1.0Lubiprostone 24 mcg Twice Daily 1.4 ± 0.8 1.5 5.7 ± 4.4 5.0 5.1 ± 4.1 4.0 5.3 ± 4.9 5.0 5.3 ± 4.7 4.0 4.3 ± 4.3 3.5 3.9 ± 4.6

3.0Study 2 Placebo 1.5 ± 0.8 1.5 4.0 ± 2.7 3.5 3.6 ± 2.7 3.0 3.4 ± 2.8 3.0 3.5 ± 2.9 3.0 2.5 ± 2.6 1.5 1.9 ± 2.7

1.5Lubiprostone 24 mcg Twice Daily 1.3 ± 0.9 1.5 5.9 ± 4.0 5.0 5.0 ± 4.2 4.0 5.6 ± 4.6 5.0 5.4 ± 4.8 4.3 4.6 ± 4.1 3.8 4.1 ± 4.8 3.0 1 Frequency rates are calculated as 7 times (number of SBMs) / (number of days observed for that week). In both studies, lubiprostone 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 lubiprostone 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 lubiprostone 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 lubiprostone during a 4-week treatment period were then randomized to receive either placebo or to continue treatment with lubiprostone. In lubiprostone-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 lubiprostone maintained their response to therapy over the additional 3 weeks of treatment.

14.2Opioid-Induced Constipation in Adults with Chronic Non-Cancer Pain The efficacy of lubiprostone 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. A… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Two 2-year oral (gavage) carcinogenicity studies (one in Crl:B6C3F1 mice and one in Sprague-Dawley rats) were conducted with lubiprostone. In the 2-year carcinogenicity study in mice, lubiprostone doses of 25, 75, 200, and 500 mcg/kg/day (approximately 2, 6, 17, and 42 times the maximum recommended human dose, respectively, based on body surface area (mg/m 2 )) were used. In the 2-year rat carcinogenicity study, lubiprostone doses of 20, 100, and 400 mcg/kg/day (approximately 3, 17, and 68 times the maximum recommended human dose, respectively, based on body surface area (mg/m 2 )) were used.

In the mouse carcinogenicity study, there was no significant increase in any tumor incidences. There was a significant increase in the incidence of interstitial cell adenoma of the testes in male rats at the 400 mcg/kg/day dose. In female rats, treatment with lubiprostone produced hepatocellular adenoma at the 400 mcg/kg/day dose.

Mutagenesis Lubiprostone was not genotoxic in the in vitro Ames reverse mutation assay, the in vitro mouse lymphoma (L5178Y TK +/− ) forward mutation assay, the in vitro Chinese hamster lung (CHL/IU) chromosomal aberration assay, and the in vivo mouse bone marrow micronucleus assay. Impairment of Fertility Lubiprostone, at oral doses of up to 1,000 mcg/kg/day, had no effect on the fertility and reproductive function of male and female rats. However, the number of implantation sites and live embryos were significantly reduced in rats at the 1,000 mcg/kg/day dose as compared to control.

The number of dead or resorbed embryos in the 1,000 mcg/kg/day group was higher compared to the control group, but was not statistically significant. The 1,000 mcg/kg/day dose in rats is approximately 169 times the maximum recommended human dose of 48 mcg/day, based on body surface area (mg/m 2 ).