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Impact of crystal polymorphism on the systemic bioavailability of rifaximin, an antibiotic acting locally in the gastrointestinal tract, in healthy volunteers.

Blandizzi C, Viscomi GC, Scarpignato C - Drug Des Devel Ther (2014)

Bottom Line: For both dose levels, peak plasma concentration, area under the concentration-time curve, and cumulative urinary excretion were significantly higher after administration of amorphous rifaximin than rifaximin-α.The few adverse events recorded were not serious and not related to the study medications.In this regard, care must be taken when using - as a medicinal product - a formulation containing even small amounts of amorphous form, which may alter the peculiar pharmacologic properties of this poorly absorbed antibiotic.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmacology and Chemotherapy, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

ABSTRACT

Background: Rifaximin is an antibiotic, acting locally in the gastrointestinal tract, which may exist in different crystal as well as amorphous forms. The current marketed rifaximin formulation contains polymorph alpha, the systemic bioavailability of which is very limited. This study compared the pharmacokinetics of this formulation with those of the amorphous form.

Methods: Amorphous rifaximin was specifically prepared for the study and formulated as the marketed product. Two doses (200 mg and 400 mg) of both formulations were given to two groups of 12 healthy volunteers of either sex according to a single-blind, randomized, two-treatment, single-dose, two-period, cross-over design. Plasma and urine samples were collected at preset times (for 24 hours or 48 hours, respectively) after dosing, and assayed for rifaximin concentrations by high-performance liquid chromatography-mass spectrometry.

Results: For both dose levels, peak plasma concentration, area under the concentration-time curve, and cumulative urinary excretion were significantly higher after administration of amorphous rifaximin than rifaximin-α. Ninety percent confidence intervals for peak plasma concentration, area under the concentration-time curve, and urinary excretion ratios were largely outside the upper limit of the accepted (0.80-1.25) range, indicating higher systemic bioavailability of the amorphous rifaximin. The few adverse events recorded were not serious and not related to the study medications.

Conclusion: Rifaximin-α, a crystal polymorph, does differ from the amorphous form, the latter being systemically more bioavailable. In this regard, care must be taken when using - as a medicinal product - a formulation containing even small amounts of amorphous form, which may alter the peculiar pharmacologic properties of this poorly absorbed antibiotic.

No MeSH data available.


Mean rifaximin concentration-time (A) and cumulative urinary excretion (B) profiles following the administration of a single 400 mg dose amorphous rifaximin or rifaximin-α to healthy volunteers. Each point or column represents the mean ± standard error of mean (vertical lines) obtained from 12 subjects.
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f4-dddt-9-001: Mean rifaximin concentration-time (A) and cumulative urinary excretion (B) profiles following the administration of a single 400 mg dose amorphous rifaximin or rifaximin-α to healthy volunteers. Each point or column represents the mean ± standard error of mean (vertical lines) obtained from 12 subjects.

Mentions: Mean plasma and urinary profiles of the two subgroups (n=12 each), treated with amorphous rifaximin or rifaximin-α, are shown in Figures 3 and 4 for the doses of 200 mg and 400 mg, respectively. The respective PK parameters are reported in Table 2. In most subjects, the first plasma concentration of rifaximin was detected at the first blood sampling (30 min after dosing) for both rifaximin formulations and doses. Concentrations then increased up to peak, which, in subjects treated with amorphous rifaximin, was achieved at 1.96 (range 0.50–12.0) hours and 1.71 (range 0.50–4.0) hours for the dose of 200 mg and 400 mg, respectively. In subjects receiving rifaximin-α, the peak was reached at 1.04 (range 0.50–2.0) hours and 1.21 (0.50–4.0) hours after dosing with 200 mg and 400 mg, respectively.


Impact of crystal polymorphism on the systemic bioavailability of rifaximin, an antibiotic acting locally in the gastrointestinal tract, in healthy volunteers.

Blandizzi C, Viscomi GC, Scarpignato C - Drug Des Devel Ther (2014)

Mean rifaximin concentration-time (A) and cumulative urinary excretion (B) profiles following the administration of a single 400 mg dose amorphous rifaximin or rifaximin-α to healthy volunteers. Each point or column represents the mean ± standard error of mean (vertical lines) obtained from 12 subjects.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4274041&req=5

f4-dddt-9-001: Mean rifaximin concentration-time (A) and cumulative urinary excretion (B) profiles following the administration of a single 400 mg dose amorphous rifaximin or rifaximin-α to healthy volunteers. Each point or column represents the mean ± standard error of mean (vertical lines) obtained from 12 subjects.
Mentions: Mean plasma and urinary profiles of the two subgroups (n=12 each), treated with amorphous rifaximin or rifaximin-α, are shown in Figures 3 and 4 for the doses of 200 mg and 400 mg, respectively. The respective PK parameters are reported in Table 2. In most subjects, the first plasma concentration of rifaximin was detected at the first blood sampling (30 min after dosing) for both rifaximin formulations and doses. Concentrations then increased up to peak, which, in subjects treated with amorphous rifaximin, was achieved at 1.96 (range 0.50–12.0) hours and 1.71 (range 0.50–4.0) hours for the dose of 200 mg and 400 mg, respectively. In subjects receiving rifaximin-α, the peak was reached at 1.04 (range 0.50–2.0) hours and 1.21 (0.50–4.0) hours after dosing with 200 mg and 400 mg, respectively.

Bottom Line: For both dose levels, peak plasma concentration, area under the concentration-time curve, and cumulative urinary excretion were significantly higher after administration of amorphous rifaximin than rifaximin-α.The few adverse events recorded were not serious and not related to the study medications.In this regard, care must be taken when using - as a medicinal product - a formulation containing even small amounts of amorphous form, which may alter the peculiar pharmacologic properties of this poorly absorbed antibiotic.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmacology and Chemotherapy, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

ABSTRACT

Background: Rifaximin is an antibiotic, acting locally in the gastrointestinal tract, which may exist in different crystal as well as amorphous forms. The current marketed rifaximin formulation contains polymorph alpha, the systemic bioavailability of which is very limited. This study compared the pharmacokinetics of this formulation with those of the amorphous form.

Methods: Amorphous rifaximin was specifically prepared for the study and formulated as the marketed product. Two doses (200 mg and 400 mg) of both formulations were given to two groups of 12 healthy volunteers of either sex according to a single-blind, randomized, two-treatment, single-dose, two-period, cross-over design. Plasma and urine samples were collected at preset times (for 24 hours or 48 hours, respectively) after dosing, and assayed for rifaximin concentrations by high-performance liquid chromatography-mass spectrometry.

Results: For both dose levels, peak plasma concentration, area under the concentration-time curve, and cumulative urinary excretion were significantly higher after administration of amorphous rifaximin than rifaximin-α. Ninety percent confidence intervals for peak plasma concentration, area under the concentration-time curve, and urinary excretion ratios were largely outside the upper limit of the accepted (0.80-1.25) range, indicating higher systemic bioavailability of the amorphous rifaximin. The few adverse events recorded were not serious and not related to the study medications.

Conclusion: Rifaximin-α, a crystal polymorph, does differ from the amorphous form, the latter being systemically more bioavailable. In this regard, care must be taken when using - as a medicinal product - a formulation containing even small amounts of amorphous form, which may alter the peculiar pharmacologic properties of this poorly absorbed antibiotic.

No MeSH data available.