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Pharmacokinetics

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

Bismuth Subcitrate Potassium (Bismuth)

Orally absorbed bismuth is distributed throughout the entire body. Bismuth is highly bound to plasma proteins (>90%). 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 µg/mL) suggesting tissue accumulation and slow elimination.

Metronidazole

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 µg/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 concentrations similar to those found in plasma.

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 urine (60% to 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/1.73 m².

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

Tetracycline is absorbed (60%-90%) 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 a biologically active form.

Tetracycline is distributed into most body tissues and fluids. It is distributed into the bile and undergoes varying degrees of enterohepatic recirculation. Tetracycline 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 (bismuth subcitrate potassium)

The clinical significance of systemic, as compared to local, drug concentrations for antimicrobial activity against Helicobacter pylori, has not been established. A comparative bioavailability study of metronidazole (375 mg), tetracycline (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, and Bismuth Subcitrate Potassium in Healthy Volunteers (N=18)

The pharmacokinetic parameters for metronidazole, tetracycline and bismuth were also determined when PYLERA™ was administered under fasting and fed conditions, as shown in Table 2. Food reduced the systemic absorption of all three PYLERA™ components, with AUC values for metronidazole, tetracycline 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. (See DOSAGE AND ADMINISTRATION)

Table 2. Mean PYLERA™ Pharmacokinetic Parameters in Fasted and Fed States (N=18)*

Omeprazole Capsules

The effect of omeprazole on bismuth absorption was assessed in 34 healthy volunteers given PYLERA™ (qid) with or without omeprazole (20 mg bid) 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 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)

Microbiology

The ingredients in PYLERA™ capsules (bismuth subcitrate potassium) are active as antibacterial agents. Tetracycline hydrochloride interacts with the 30S subunit of the bacterial ribosome and inhibits protein synthesis. Metronidazole is metabolized through reductive pathways into reactive intermediates that have cytotoxic action. The antibacterial action of bismuth salts is not well understood.

PYLERA™ plus omeprazole therapy has been shown to be active against most strains of Helicobacter pylori in vitro, and in clinical infections as described in the CLINICAL STUDIES and INDICATIONS AND USAGE sections.

Susceptibility Testing for Helicobacter pylori

Susceptibility testing of Helicobacter pylori isolates was performed for metronidazole using agar dilution methodology according to CLSI¹ guidelines 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.

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.

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

• Three (3) PYLERA™ capsules (bismuth subcitrate potassium) four times daily, after meals and at bedtime plus 20 mg omeprazole twice a day after breakfast and supper (OBMT).
• Clarithromycin 500 mg plus 1000 mg amoxicillin plus 20 mg omeprazole twice a day before breakfast and supper (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 4 for OBMT and OAC. The eradication rates for both groups were found to be similar using either the Modified Intent-to-Treat (MITT) or Per Protocol (PP) populations.

Table 4. Helicobacter pylori Eradication at 8 Weeks after 10 Day Treatment Regimen Percent (%) of Patients Cured [95% Confidence Interval] (Number of Patients)

REFERENCES

1. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard --Seventh Edition. Clinical and Laboratory Standards Institute document M7-A7, Vol. 26, No. 2, CLSI, Wayne, PA, January 2006.

Last reviewed on RxList: 6/13/2007
This monograph has been modified to include the generic and brand name in many instances.