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Kapidex (Dexlansoprazole) - Description and Clinical Pharmacology

 
 



DESCRIPTION

The active ingredient in KAPIDEX (dexlansoprazole) delayed release capsules is (+)-2-[(R)-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl} sulfinyl]-1H-benzimidazole, a compound that inhibits gastric acid secretion. Dexlansoprazole is the R-enantiomer of lansoprazole (a racemic mixture of the R- and S-enantiomers). Its empirical formula is: C16H14F3N3O2S, with a molecular weight of 369.36. The structural formula is:

Dexlansoprazole is a white to nearly white crystalline powder which melts with decomposition at 140°C. Dexlansoprazole is freely soluble in dimethylformamide, methanol, dichloromethane, ethanol, and ethyl acetate; and soluble in acetonitrile; slightly soluble in ether; and very slightly soluble in water; and practically insoluble in hexane.

Dexlansoprazole is stable when exposed to light. Dexlansoprazole is more stable in neutral and alkaline conditions than acidic conditions.

KAPIDEX is supplied as a dual delayed release formulation in capsules for oral administration. The capsules contain dexlansoprazole in a mixture of two types of enteric-coated granules with different pH-dependent dissolution profiles [see Clinical Pharmacology ].

KAPIDEX is available in two dosage strengths: 30 mg and 60 mg, per capsule. Each capsule contains enteric-coated granules consisting of dexlansoprazole (active ingredient) and the following inactive ingredients: sugar spheres, magnesium carbonate, sucrose, low-substituted hydroxypropyl cellulose, titanium dioxide, hydroxypropyl cellulose, hypromellose 2910, talc, methacrylic acid copolymer, polyethylene glycol 8000, triethyl citrate, polysorbate 80, and colloidal silicon dioxide. The components of the capsule shell include the following inactive ingredients: hypromellose, carrageenan and potassium chloride. Based on the capsule shell color, blue contains FD&C Blue No. 2 and aluminum lake; gray contains ferric oxide and aluminum lake; and both contain titanium dioxide.

CLINICAL PHARMACOLOGY

Antisecretory Activity

The effects of KAPIDEX 60 mg (n = 20) or lansoprazole 30 mg (n = 23) once daily for five days on 24-hour intragastric pH were assessed in healthy subjects in a multiple-dose crossover study. The results are summarized in Table 3.

Table 3: Effect on 24-hour Intragastric pH on Day 5 After Administration of KAPIDEX or Lansoprazole

KAPIDEX 60 mg Lansoprazole 30 mg
Mean Intragastric pH
4.55 4.13
% Time Intragastric pH > 4
(hours)
71
(17 hours)
60
(14 hours)
Serum Gastrin Effects

The effect of KAPIDEX on serum gastrin concentrations was evaluated in approximately 3460 patients in clinical trials up to 8 weeks and in 1023 patients for up to 6 to 12 months. The mean fasting gastrin concentrations increased from baseline during treatment with KAPIDEX 30 mg and 60 mg doses. In patients treated for more than 6 months, mean serum gastrin levels increased during approximately the first 3 months of treatment and were stable for the remainder of treatment. Mean serum gastrin levels returned to pre-treatment levels within one month of discontinuation of treatment.

Enterochromaffin-Like Cell (ECL) Effects

There were no reports of ECL cell hyperplasia in gastric biopsy specimens obtained from 653 patients treated with KAPIDEX 30 mg, 60 mg or 90 mg for up to 12 months.

During lifetime exposure of rats dosed daily with up to 150 mg per kg per day of lansoprazole, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats [see Nonclinical Toxicology ].

Effect on Cardiac Repolarization

A study was conducted to assess the potential of KAPIDEX to prolong the QT/QTc interval in healthy adult subjects. KAPIDEX doses of 90 mg or 300 mg did not delay cardiac repolarization compared to placebo. The positive control (moxifloxacin) produced statistically significantly greater mean maximum and time-averaged QT/QTc intervals compared to placebo.

Figure 1). Dexlansoprazole is eliminated with a half-life of approximately 1 to 2 hours in healthy subjects and in patients with symptomatic GERD. No accumulation of dexlansoprazole occurs after multiple, once daily doses of KAPIDEX 30 mg or 60 mg, although mean AUCt and Cmax values of dexlansoprazole were slightly higher (less than 10%) on day 5 than on day 1.

Figure 1: Mean Plasma Dexlansoprazole Concentration –
Time Profile Following Oral Administration of 30 or 60 mg KAPIDEX
Once Daily for 5 Days in Healthy Subjects

The pharmacokinetics of dexlansoprazole are highly variable, with percent coefficient of variation (CV%) values for Cmax, AUC, and CL/F of greater than 30% (see Table 4).

Table 4: Mean (CV%) Pharmacokinetic Parameters for Subjects on Day 5 After Administration of KAPIDEX
Dose
(mg)
Cmax
(ng/mL)
AUC24
(ng∙h/mL)
CL/F
(L/h)
30 658 (40%)
(N=44)
3275 (47%)
(N=43)
11.4 (48%)
(N=43)
60 1397 (51%)
(N=79)
6529 (60%)
(N=73)
11.6 (46%)
(N=41)

Absorption

After oral administration of KAPIDEX 30 mg or 60 mg to healthy subjects and symptomatic GERD patients, mean Cmax and AUC values of dexlansoprazole increased approximately dose proportionally (see Figure 1).

Distribution

Plasma protein binding of dexlansoprazole ranged from 96.1% to 98.8% in healthy subjects and was independent of concentration from 0.01 to 20 mcg per mL. The apparent volume of distribution (Vz/F) after multiple doses in symptomatic GERD patients was 40.3 L.

Metabolism

Dexlansoprazole is extensively metabolized in the liver by oxidation, reduction, and subsequent formation of sulfate, glucuronide and glutathione conjugates to inactive metabolites. Oxidative metabolites are formed by the cytochrome P450 (CYP) enzyme system including hydroxylation mainly by CYP2C19, and oxidation to the sulfone by CYP3A4.

CYP2C19 is a polymorphic liver enzyme which exhibits three phenotypes in the metabolism of CYP2C19 substrates; extensive metabolizers (*1/*1), intermediate metabolizers (*1/mutant) and poor metabolizers (mutant/mutant). Dexlansoprazole is the major circulating component in plasma regardless of CYP2C19 metabolizer status. In CYP2C19 intermediate and extensive metabolizers, the major plasma metabolites are 5-hydroxy dexlansoprazole and its glucuronide conjugate, while in CYP2C19 poor metabolizers dexlansoprazole sulfone is the major plasma metabolite.

Elimination

Following the administration of KAPIDEX, no unchanged dexlansoprazole is excreted in urine. Following the administration of [14C]dexlansoprazole to 6 healthy male subjects, approximately 50.7% (standard deviation (SD): 9.0%) of the administered radioactivity was excreted in urine and 47.6% (SD: 7.3%) in the feces. Apparent clearance (CL/F) in healthy subjects was 11.4 to 11.6 L/h, respectively, after 5-days of 30 or 60 mg once daily administration.

Effect of CYP2C19 Polymorphism on Systemic Exposure of Dexlansoprazole

Systemic exposure of dexlansoprazole is generally higher in intermediate and poor metabolizers. In male Japanese subjects who received a single dose of KAPIDEX 30 mg or 60 mg (N=2 to 6 subjects/group), mean dexlansoprazole Cmax and AUC values were up to 2 times higher in intermediate compared to extensive metabolizers; in poor metabolizers, mean Cmax was up to 4 times higher and mean AUC was up to 12 times higher compared to extensive metabolizers. Though such study was not conducted in Caucasians and African Americans, it is expected dexlansoprazole exposure in these races will be affected by CYP2C19 phenotypes as well.

12.4 Effect of Food on Pharmacokinetics and Pharmacodynamics

In food-effect studies in healthy subjects receiving KAPIDEX under various fed conditions compared to fasting, increases in Cmax ranged from 12% to 55%, increases in AUC ranged from 9% to 37%, and tmax varied (ranging from a decrease of 0.7 hours to an increase of 3 hours). No significant differences in mean intragastric pH were observed between fasted and various fed conditions. However, the percentage of time intragastric pH exceeded 4 over the 24-hour dosing interval decreased slightly when KAPIDEX was administered after a meal (57%) relative to fasting (64%), primarily due to a decreased response in intragastric pH during the first 4 hours after dosing. Because of this, while KAPIDEX can be taken without regard to food, some patients may benefit from administering the dose prior to a meal if post-meal symptoms do not resolve under post-fed conditions.

12.5 Special Populations

Pediatric Use

The pharmacokinetics of dexlansoprazole in patients under the age of 18 years have not been studied.

Geriatric Use

The terminal elimination half-life of dexlansoprazole is significantly increased in geriatric subjects compared to younger subjects (2.23 and 1.5 hours, respectively); this difference is not clinically relevant. Dexlansoprazole exhibited higher systemic exposure (AUC) in geriatric subjects (34.5% higher) than younger subjects. No dosage adjustment is needed in geriatric patients [see Use in Specific Populations ].

Renal Impairment

Dexlansoprazole is extensively metabolized in the liver to inactive metabolites, and no parent drug is recovered in the urine following an oral dose of dexlansoprazole. Therefore, the pharmacokinetics of dexlansoprazole are not expected to be altered in patients with renal impairment, and no studies were conducted in subjects with renal impairment [see Use in Specific Populations ]. In addition, the pharmacokinetics of lansoprazole were studied in patients with mild, moderate or severe renal impairment; results demonstrated no need for a dose adjustment for this patient population.

Hepatic Impairment

In a study of 12 patients with moderately impaired hepatic function who received a single oral dose of KAPIDEX 60 mg, plasma exposure (AUC) of bound and unbound dexlansoprazole in the hepatic impairment group was approximately 2 times greater compared to subjects with normal hepatic function. This difference in exposure was not due to a difference in protein binding between the two liver function groups. No adjustment for KAPIDEX is necessary for patients with mild hepatic impairment (Child-Pugh Class A). KAPIDEX 30 mg should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations ].

Gender

In a study of 12 male and 12 female healthy subjects who received a single oral dose of KAPIDEX 60 mg, females had higher systemic exposure (AUC) (42.8% higher) than males. No dosage adjustment is necessary in patients based on gender.

12.6 Drug-Drug Interactions

Warfarin

In a study of 20 healthy subjects, co-administration of KAPIDEX 90 mg once daily for 11 days with a single 25 mg oral dose of warfarin on day 6 did not result in any significant differences in the pharmacokinetics of warfarin or INR compared to administration of warfarin with placebo. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly [see Drug Interactions ].

Cytochrome P 450 Interactions

Dexlansoprazole is metabolized, in part, by CYP2C19 and CYP3A4 [see Clinical Pharmacology ].

In vitro studies have shown that KAPIDEX is not likely to inhibit CYP isoforms 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4. As such, no clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Furthermore, clinical drug-drug interaction studies in mainly CYP2C19 extensive and intermediate metabolizers have shown that KAPIDEX does not affect the pharmacokinetics of diazepam, phenytoin, or theophylline. The subjects' CYP1A2 genotypes in the drug-drug interaction study with theophylline were not determined.


NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of dexlansoprazole was assessed using lansoprazole studies. In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally with lansoprazole at doses of 5 to 150 mg per kg per day, about 1 to 40 times the exposure on a body surface (mg/m2) basis of a 50 kg person of average height (1.46 m2 BSA) given the recommended human dose of lansoprazole (30 mg per day).

Lansoprazole produced dose-related gastric ECL cell hyperplasia and ECL cell carcinoids in both male and female rats [see Clinical Pharmacology ].

In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg per kg per day (4 to 40 times the recommended lansoprazole human dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat. Testicular interstitial cell adenoma also occurred in 1 of 30 rats treated with 50 mg lansoprazole per kg per day (13 times the recommended lansoprazole human dose based on BSA) in a 1-year toxicity study.

In a 24-month carcinogenicity study, CD-1 mice were treated orally with lansoprazole doses of 15 mg to 600 mg per kg per day, 2 to 80 times the recommended human dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 mg and 600 mg lansoprazole per kg per day (40 to 80 times the recommended lansoprazole human dose based on BSA) and female mice treated with 150 mg to 600 mg lansoprazole per kg per day (20 to 80 times the recommended human dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg per kg per day (10 to 80 times the recommended lansoprazole human dose based on BSA).

A 26-week p53 (+/-) transgenic mouse carcinogenicity study of lansoprazole was not positive.

Lansoprazole was negative in the Ames test, the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus test and the rat bone marrow cell chromosomal aberration test. Lansoprazole was positive in in vitro human lymphocyte chromosomal aberration tests.

Dexlansoprazole was positive in the Ames test and in the in vitro chromosome aberration test using Chinese hamster lung cells. Dexlansoprazole was negative in the in vivo mouse micronucleus test.

The potential effects of dexlansoprazole on fertility and reproductive performance were assessed using lansoprazole studies. Lansoprazole at oral doses up to 150 mg per kg per day (40 times the recommended lansoprazole human dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats.

CLINICAL STUDIES

14.1 Healing of Erosive Esophagitis

Two multi-center, double-blind, active-controlled, randomized, 8-week studies were conducted in patients with endoscopically confirmed EE. Severity of the disease was classified based on the Los Angeles Classification Grading System (Grades A-D). Patients were randomized to one of the following three treatment groups: KAPIDEX 60 mg daily, KAPIDEX 90 mg daily or lansoprazole 30 mg daily. Patients who were H pylori positive or who had Barrett's Esophagus and/or definite dysplastic changes at baseline were excluded from these studies. A total of 4092 patients were enrolled and ranged in age from 18 to 90 years (median age 48 years) with 54% male. Race was distributed as follows: 87% Caucasian, 5% Black and 8% other. Based on the Los Angeles Classification, 71% of patients had mild EE (Grades A and B) and 29% of patients had moderate to severe EE (Grades C and D) before treatment.

The studies were designed to test non-inferiority. If non-inferiority was demonstrated then superiority would be tested. Although non-inferiority was demonstrated in both studies, the finding of superiority in one study was not replicated in the other.

The proportion of patients with healed EE at week 4 or 8 is presented below in Table 5.

Table 5: EE Healing Rates*: All Grades
Study Number of Patients
(N) †
Treatment Group
(daily)
Week 4
% Healed
Week 8 ‡
% Healed
(95% CI) for the Treatment
Difference (KAPIDEX –
Lansoprazole) by Week 8

1

657
KAPIDEX 60 mg
70
87

(-1.5, 6.1) §

648
Lansoprazole 30 mg
65
85


2
639
KAPIDEX 60 mg
66
85

(2.2, 10.5) §

656
Lansoprazole 30 mg
65
79

CI = Confidence interval
*   
Based on crude rate estimates, patients who did not have endoscopically documented healed EE and prematurely discontinued were considered not healed. †    Patients with at least one post baseline endoscopy
‡    Primary efficacy endpoint
§    Demonstrated non-inferiority to lansoprazole


KAPIDEX 90 mg was studied and did not provide additional clinical benefit over KAPIDEX 60 mg.

14.2 Maintenance of Healed Erosive Esophagitis

A multi-center, double-blind, placebo-controlled, randomized study was conducted in patients who successfully completed an EE study and showed endoscopically confirmed healed EE. Maintenance of healing and symptom resolution over a six-month period were evaluated with KAPIDEX 30 mg or 60 mg once daily compared to placebo. A total of 445 patients were enrolled and ranged in age from 18 to 85 years (median age 49 years), with 52% female. Race was distributed as follows: 90% Caucasian, 5% Black and 5% other.

Sixty-six percent of patients treated with 30 mg of KAPIDEX remained healed over the six-month time period as confirmed by endoscopy (see Table 6).

Table 6: Maintenance Rates* of Healed EE at Month 6
Number of Patients
(N) †
Treatment Group
(daily)
Maintenance Rate
(%)
125
KAPIDEX 30 mg
66.4 ‡
119
Placebo
14.3
*  
Based on crude rate estimates, patients who did not have endoscopically documented relapse and prematurely discontinued were considered to have relapsed. †    Patients with at least one post baseline endoscopy ‡   
Statistically significant vs placebo

KAPIDEX 60 mg was studied and did not provide additional clinical benefit over KAPIDEX 30 mg.

KAPIDEX 30 mg demonstrated a higher median percent of 24-hour heartburn-free days compared to placebo over the 6-month treatment period.

14.3 Symptomatic Non-Erosive GERD

A multi-center, double-blind, placebo-controlled, randomized, 4-week study was conducted in patients with a diagnosis of symptomatic non-erosive GERD made primarily by presentation of symptoms. These patients who identified heartburn as their primary symptom, had a history of heartburn for 6 months or longer, had heartburn on at least 4 of 7 days immediately prior to randomization and had no esophageal erosions as confirmed by endoscopy. However, patients with symptoms which were not acid-related may not have been excluded using these inclusion criteria. Patients were randomized to one of the following treatment groups: KAPIDEX 30 mg daily, 60 mg daily, or placebo. A total of 947 patients were enrolled and ranged in age from 18 to 86 years (median age 48 years) with 71% female. Race was distributed as follows: 82% Caucasian, 14% Black and 4% other.

KAPIDEX 30 mg provided statistically significantly greater percent of days with heartburn-free 24-hour periods over placebo as assessed by daily diary over 4 weeks (see Table 7). KAPIDEX 60 mg was studied and provided no additional clinical benefit over KAPIDEX 30 mg.

Table 7: Median Percentages of 24-Hour Heartburn-Free Periods During the 4 Week Treatment Period of the Symptomatic Non-Erosive GERD Study
N
Treatment Group
(daily)
Heartburn-Free
24-hour Periods
(%)
312
KAPIDEX 30 mg
54.9*
310
Placebo
18.5

*  Statistically significant vs placebo

A higher percentage of patients on KAPIDEX 30 mg had heartburn-free 24-hour periods compared to placebo as early as the first three days of treatment and this was sustained throughout the treatment period (percentage of patients on Day 3: KAPIDEX 38% versus placebo 15%; on Day 28: KAPIDEX 63% versus placebo 40%).



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