Pylera - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Pylera - Scientific Information

Manufacture: Forest Laboratories, Inc.
Country: United States
Condition: Helicobacter Pylori Infection
Class: H. pylori eradication agents
Form: Capsules
Ingredients: bismuth subcitrate potassium, metronidazole, tetracycline hydrochloride, magnesium stearate (E572), lactose monohydrate, talc (E553b), titanium dioxide (E171), gelatin and printing ink containing shellac, propylene glycol and red iron oxide (E172)

Description

PYLERA capsules are a combination antimicrobial product containing bismuth subcitrate potassium, metronidazole, and tetracycline hydrochloride for oral administration. Each size 0 elongated capsule contains:

  • bismuth subcitrate potassium, 140 mg
  • metronidazole, 125 mg
  • smaller capsule (size 3) containing tetracycline hydrochloride, 125 mg

Tetracycline hydrochloride is encapsulated within a smaller capsule to create a barrier to avoid contact with bismuth subcitrate potassium.

Each PYLERA capsule contains the following inactive ingredients: Magnesium Stearate NF, Lactose Monohydrate NF, Talc USP, Gelatin USP, and Titanium Dioxide NF. Printed in red ink.

Bismuth subcitrate potassium is a white or almost white powder. It is a soluble, complex bismuth salt of citric acid. The schematized empirical molecular formula of bismuth subcitrate potassium is Bi (Citrate)2K5●3 H2O. The equivalent theoretical molecular formula is BiC12H14K5O17. The molecular mass of the theoretical molecular formula of a single unit of bismuth subcitrate potassium is 834.71.

Metronidazole is a white to pale yellow crystalline powder. Metronidazole is 2-methyl-5-nitroimidazole-1-ethanol, with a molecular formula of C6H9N3O3 and the following structural formula:


Tetracycline hydrochloride is a yellow, odorless, crystalline powder. Tetracycline hydrochloride is stable in air, but exposure to strong sunlight causes it to darken. Tetracycline hydrochloride is (4S,4aS,5aS,6S,12aS)-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-penta-hydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrochloride, with a molecular formula of C22H24N2O8●HCl and the following structural formula:


Clinical Pharmacology

Mechanism of Action

PYLERA, a combination of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride is an antibacterial agent [See Clinical Pharmacology].

Pharmacokinetics

The pharmacokinetics of the individual components of PYLERA, bismuth subcitrate potassium, metronidzole, tetracycline hydrochloride, are summarized below. In addition, two studies on PYLERA were conducted to determine the effect of co-administration on the pharmacokinetics of the components.

Bismuth Subcitrate Potassium (Bismuth)

Absorption and Distribution

Orally absorbed bismuth is distributed throughout the entire body. Bismuth is highly bound to plasma proteins (>90%).

Metabolism and Excretion

The elimination half-life of bismuth is approximately 5 days in both blood and urine. Elimination of bismuth is primarily through urinary and biliary routes. The rate of renal elimination appears to reach steady state 2 weeks after treatment discontinuation with similar rates of elimination at 6 weeks after discontinuation. The average urinary elimination of bismuth is 2.6% per day in the first two weeks after discontinuation (urine drug concentrations 24 to 250 mcg/mL) suggesting tissue accumulation and slow elimination.

Metronidazole

Absorption and Distribution

Following oral administration, metronidazole is well absorbed, with peak plasma concentrations occurring between 1 and 2 hours after administration. Plasma concentrations of metronidazole are proportional to the administered dose, with oral administration of 500 mg producing a peak plasma concentration of 12 mcg/mL.

Metronidazole appears in the plasma mainly as unchanged compound with lesser quantities of the 2-hydroxymethyl metabolite also present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole also appears in cerebrospinal fluid, saliva, and breast milk in concentration similar to those found in plasma.

Metabolism and Excretion

The average elimination half-life of metronidazole in normal volunteers is 8 hours. The major route of elimination of metronidazole and its metabolites is via the urineto 80% of the dose), with fecal excretion accounting for 6% to 15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-(β-hydroxyethyl) 2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/min/1.73m2.

Decreased renal function does not alter the single dose pharmacokinetics of metronidazole. In patients with decreased liver function, plasma clearance of metronidazole is decreased.

Tetracycline Hydrochloride

Absorption, Distribution, Metabolism and Excretion

Tetracycline hydrochloride is absorbed90%) in the stomach and upper small intestine. The presence of food, milk or cations may significantly decrease the extent of absorption. In the plasma, tetracycline is bound to plasma proteins in varying degrees. It is concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in biologically active form.

Tetracycline hydrochloride is distributed into most body tissues and fluids. It is distributed into the bile and undergoes varying degrees of enterohepatic recirculation. Tetracycline hydrochloride tends to localize in tumors, necrotic or ischemic tissue, liver and spleen and form tetracycline-calcium orthophosphate complexes at sites of new bone formation or tooth development. Tetracycline readily crosses the placenta and is excreted in high amounts in breast milk.

PYLERA Capsules

A comparative bioavailability study of metronidazole (375 mg), tetracycline hydrochloride (375 mg) and bismuth subcitrate potassium (420 mg, equivalent to 120 mg Bi2O3) administered as PYLERA or as 3 separate capsule formulations administered simultaneously was conducted in healthy male volunteers. The pharmacokinetic parameters for the individual drugs, when administered as separate capsule formulations or as PYLERA, are similar as shown in Table 1.

Table 1: Mean (%CV) Pharmacokinetic Parameters for Metronidazole, Tetracycline hydrochloride, and Bismuth Subcitrate Potassium in Healthy Volunteers (N=18)
    Cmax(ng/mL) (%C.V.*) AUCT(ng · h/mL) (%C.V.*) AUC(ng · h/mL) (%C.V.*)
Metronidazole Metronidazole Capsule 9044 (20) 80289 (15) 81849 (16)
  PYLERA† 8666.3 (22) 83018 (17) 84413 (17)
Tetracycline Tetracycline Capsules 748.0 (40) 9544 (55) 9864 (53)
  PYLERA† 774 (47) 9674 (50) 9987 (49)
Bismuth Bismuth Capsule 22 (123) 47 (129) 65.4 (113)
  PYLERA† 17 (202) 43 (191) 57 (178)
* C.V. – Coefficient Variation
† PYLERA given as a single dose of 3 capsules

Effect of Bismuth on the Bioavailability of Tetracycline Hydrochloride

There is an anticipated reduction in tetracycline hydrochloride systemic absorption due to an interaction with bismuth. The effect of a reduced tetracycline hydrochloride systemic exposure, due to an interaction with bismuth, on the clinical efficacy of PYLERA is not thought to be clinically meaningful as the contribution of systemic, as compared to local, antimicrobial activity against Helicobacter pylorihas not been established.

Effect of Food on the Bioavailability of PYLERA

The pharmacokinetic parameters for metronidazole, tetracycline hydrochloride and bismuth were also determined when PYLERA was administered under fasting and fed conditions, as shown in Table 4. Food reduced the systemic absorption of all three PYLERA components, with AUC values for metronidazole, tetracycline hydrochloride and bismuth being reduced by 6%, 34% and 60%, respectively. Reduction in the absorption of all three PYLERA components in the presence of food is not considered to be clinically significant. PYLERA should be given after meals and at bedtime, in combination with omeprazole twice a day.

Table 2: Mean PYLERA Pharmacokinetic Parameters in Fasted and Fed States (N=18)*
  FED FASTED
  metronidazole tetracycline bismuth metronidazole tetracycline bismuth
Cmax (ng/mL)(%C.V.) 6835.0
(13)
515.8
(36)
1.7
(61)
8666.3
(22)
773.8
(47)
16.7
(202)
Tmax (hours)†(range) 3.0
(1.3 – 4.0)
4.0
(2.5 – 5.0)
3.5
(0.8 – 6.0)
0.75
(0.5 - 3.5)
3.3
(1.3 – 5.0)
0.6
(0.5 – 1.7)
AUC (ng · h/mL)(%C.V.) 79225.6
(18)
5840.1
(312)
18.4
(116)
84413.6
(17)
9986.7
(49)
56.5
(178)
* PYLERA given as a single dose of 3 capsules
† T max is expressed as median (range)

Effect of Omeprazole on the Bioavailability of Bismuth

The effect of omeprazole on bismuth absorption was assessed in 34 healthy volunteers given PYLERA (four times daily) with or without omeprazole (20 mg twice daily) for 6 days. In the presence of omeprazole, the extent of absorption of bismuth from PYLERA was significantly increased, compared to when no omeprazole was given (Table 3 ). Concentration-dependent neurotoxicity is associated with long-term use of bismuth and not likely to occur with short-term administration or at steady state concentrations below 50 ng/mL. One subject transiently achieved a maximum bismuth concentration (Cmax) higher than 50 ng/mL (73 ng/mL) following multiple dosing of PYLERA with omeprazole. The patient did not exhibit symptoms of neurotoxicity during the study. There is no clinical evidence to suggest that short-term exposure to bismuth Cmax concentrations above 50 ng/mL is associated with neurotoxicity.

Table 3: Mean Bismuth Pharmacokinetic Parameters following PYLERA Administration* With and Without Omeprazole (N=34)
Parameter Without omeprazole With omeprazole
Mean %C.V.† Mean %C.V.†
Cmax(ng/mL) 8.1 84 25.5 69
AUCT(ng · h/mL) 48.5 28 140.9 42
* PYLERA given as 3 capsules four times daily for 6 days with or without 20 mg omeprazole twice daily
†C.V. – Coefficient Variation

Microbiology

Mechanism of Action

PYLERA, a combination of bismuth subcitrate potassium, metronidazole and tetracycline hydrochloride has antibacterial activity. Metronidazole is metabolized through reductive pathways into reactive intermediates that have cytotoxic action. Tetracycline hydrochloride interacts with the 30S subunit of the bacterial ribosome and inhibits protein synthesis. The antibacterial action of bismuth salts is not well understood.

Activity in vitro and in vivo 

PYLERA plus omeprazole therapy has been shown to be active against most strains of Helicobacter pylori both in vitro and in clinical infections [See Clinical Studies].

Susceptibility Test Methods

Dilution techniques

Susceptibility testing of Helicobacter pylori isolates was performed for metronidazole using agar dilution methodology according to CLSI1 guidelines [See References], and minimum inhibitory concentrations (MICs) were determined.

Susceptibility testing of Helicobacter pylori for metronidazole has not been standardized. No interpretive criteria have been established for testing metronidazole against H. pylori.

The clinical significance of metronidazole MIC values against H. pylori is unknown. In the North American study, pre-treatment metronidazole MIC values showed no correlation with clinical outcome in patients treated with PYLERA and omeprazole therapy.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies have been performed to evaluate the effect of PYLERA on carcinogenesis, mutagenesis, or impairment of fertility.

Bismuth Subcitrate Potassium

No carcinogenicity or reproductive toxicity studies have been conducted with bismuth subcitrate potassium. Bismuth subsalicylate did not show mutagenic potential in the NTP Salmonella plate assay.

Metronidazole

Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic, oral administration in mice and rats. Prominent among the effects in the mouse was an increased incidence of pulmonary tumorigenesis. This has been observed in all six reported studies in that species, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). At the highest dose levels, (approximately 500 mg/kg/day, which is approximately 1.6 times the indicated human dose for a 60 kg adult based on body surface area), there was a statistically significant increase in the incidence of malignant liver tumors in male mice. Also, the published results of one of the mouse studies indicate an increase in the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime feeding of the drug. All these effects are statistically significant. Long-term, oral-dosing studies in the rat showed statistically significant increases in the incidence of various neoplasms, particularly in mammary and hepatic tumors, among female rats administered metronidazole over those noted in the concurrent female control groups. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative. Although metronidazole has shown mutagenic activity in a number of in vitro assay systems, studies in mammals (in vivo) have failed to demonstrate a potential for genetic damage.

Fertility studies have been conducted with male rates and mice with divergent results. Metronidazole, at doses up to 400 mg/kg/day (approximately 3 times the indicated human dose based on mg/m2) for 28 days, failed to produce any adverse effects on fertility and testicular function in male rats. In another study where rats were treated with up to 400 mg/kg/day for 8 weeks, there was severe degeneration of the seminiferous epithelium in the testes which was associated with a marked decrease in testicular spermatid counts and epididymal sperm counts and a marked decrease in fecundity. These effects were partially reversible.

Fertility studies have been performed in male mice at doses up to six times the maximum recommended human dose based upon mg/m2 and have revealed no evidence of impaired fertility. Another fertility study was performed in male mice at oral doses of 500 mg/kg/day (approximately 2 times the indicated human dose based on mg/m2) for 14 days. Metronidazole significantly decreased testes and epididymides weight, decreased sperm viability, and increased the incidence of abnormal sperm. The viability of sperm was normal by 2 months after the start of the treatment.

Tetracycline hydrochloride

There has been no evidence of carcinogenicity for tetracycline hydrochloride in studies conducted with rats and mice. Some related antibiotics (oxytetracycline, minocycline) have shown evidence of oncogenic activity in rats.

There was evidence of mutagenicity by tetracycline hydrochloride in two in vitro mammalian cell assay systems (L51784y mouse lymphoma and Chinese hamster lung cells).

Tetracycline hydrochloride had no effect on fertility when administered in the diet to male and female rats at a daily intake of 25 times the human dose.

Clinical Studies

Eradication of Helicobacter pylori in Patients with Active Duodenal Ulcer or History of Duodenal Ulcer Disease

An open-label, parallel group, active-controlled, multicenter study in Helicobacter pylori positive patients with current duodenal ulcer or a history of duodenal ulcer disease was conducted in the United States and Canada (the North American Study).

Patients were randomized to one of the following 10-day treatment regimens:

  • Three (3) PYLERA capsules four times daily, after meals and at bedtime plus 20 mg omeprazole twice a day after the morning and evening meals (OBMT).
  • Clarithromycin 500 mg plus 1000 mg amoxicillin plus 20 mg omeprazole twice a day before the morning and evening meals (OAC).

H. pylori eradication rates, defined as two negative 13C-urea breath tests performed at 4 and 8 weeks post-therapy are shown in Table 6 for OBMT and OAC. The eradication rates for both groups were found to be similar using either the Per Protocol (PP) or Modified Intent-to-Treat (MITT) populations.

Table 4: Helicobacter pylori Eradication at 8 Weeks after 10 Day Treatment Regimen Percent (%) of Patients Cured [95% Confidence Interval] (Number of Patients)
  Treatment Group Difference
  OBMT* OAC†‡  
Per Protocol§ 92.5%
[87.8, 97.2]
(n=120)
85.7%
[76.9, 91.8]
(n=126)
6.8%
[-0.9, 14.5]
Modified Intent-to-Treat¶ 87.7%
[82.2, 93.2]
(n=138)
83.2%
[77.0, 89.5]
(n=137)
4.5%
[-3.9, 12.8]
* OBMT: Omeprazole + PYLERA (bismuth subcitrate potassium / metronidazole / tetracycline hydrochloride)
OAC: Omeprazole + Amoxicillin + Clarithromycin
‡ Results for OAC treatment represent all isolates regardless of clarithromycin susceptibility. Eradication rates for clarithromycin susceptible organisms, as defined by an MIC ≤ 0.25 mcg/mL, were 94.6% and 92.1% for the PP and MITT analysis, respectively. Eradication rates for clarithromycin non-susceptible organisms, as defined by an MIC ≥ 0.5 mcg/mL, were 23.1% and 21.4% for the PP and MITT analysis, respectively.
§ Patients were included in the PP analysis if they had H. pylori infection documented at baseline, defined as a positive 13C-UBT plus histology or culture, had at least one endoscopically verified duodenal ulcer ≥ 0.3 cm at baseline or had a documented history of duodenal ulcer disease, and were not protocol violators. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the evaluable analysis as failures of therapy.
¶ Patients were included in the MITT analysis if they had documented H. pylori infection at baseline as defined above, and had at least one documented duodenal ulcer at baseline or had a documented history of duodenal ulcer disease, and took at least one dose of study medication. All dropouts were included as failures of therapy.