ABSTRACT
Title
Difference in bioavailability of commercially available rifaximin equivalent drugs.
Authors
A. Giusti1, A. Marzo1, V. Lauro 2
1 I.P.A.S. S.A. – Institute for Pharmacokinetic and Analytical Studies – Via Mastri 36 – 6853 Ligornetto, Switzerland; 2 Alfa Wassermann – Clinical Research Dept. – Via Ragazzi del ’99 – 40133 Bologna, Italy.
1 I.P.A.S. S.A. – Institute for Pharmacokinetic and Analytical Studies – Via Mastri 36 – 6853 Ligornetto, Switzerland; 2 Alfa Wassermann – Clinical Research Dept. – Via Ragazzi del ’99 – 40133 Bologna, Italy.
Abstract
Introduction: Polymorphism is the ability of compounds in solid status to exhibit different arrangements and/or conformations of the molecules in crystal lattice. It could have a direct impact upon drug product quality/performance, such as stability, dissolution, and bioavailability. Rifaximin, a rifamycin analogue, is a powerful agent, negligibly absorbed after oral administration, with a broad spectrum of antibacterial activity on Gram-positive and Gram-negative, aerobic and anaerobic bacteria, comparable, in vitro, to that of rifampicin. Rifaximin-α is the polymorphic form of the active ingredient contained in the product Normix®, commercially available as 200 mg film-coated tablet in Italy, in several other European countries and also marketed in United States since 2004 under the brand name of Xifaxan®. Only recently, generic drugs of Rifaximin, of which the polymorphic form is not stated in the SmPC, are available in Italy.
Methods: Twenty-four healthy volunteers were enrolled in a clinical pharmacology, single-dose, two-treatment, cross-over study and randomised to receive oral doses of Rifaximin polymorph-α and a generic of Rifaximin on the market, after an overnight fast with at least 7 days’ wash-out between sequences. PK assessments were performed evaluating plasma and urine rifaximin levels by liquid chromatography-tandem mass spectrometry on samples collected at the following times: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 and 24 hours post-dosing for blood and 0 (from awakening until drug administration), 0-4, 4-8, 8-12, 12-24, 24-48 hours post-dosing for urine. The systemic absorption of the two rifaximin products was considered equivalent when Cmax, Aeo-t, AUC0-∞ 90% CIs were within the interval 0.80-1.25.
Results: Rifaximin-α and generic Rifaximin PK parameters are reported in the following table with relative 90% CIs.
Conclusions: Generic Rifaximin 200 mg film-coated tablet administered as single oral 400 mg dose to healty volunteers in fasting condition showed higher plasma concentrations when compared to Rifaximin-α 200 mg film-coated tablet, administered at the same dose, leading to plasma concentrations and PK parameters of the active compound 3-4 times higher than dose calculated with Rifaximin-α. These results could be most likely justified by differences in polymorphism of the active ingredient. Different bioavailability could lead to different therapeutic efficacy and safety profile in clinical practice.
Methods: Twenty-four healthy volunteers were enrolled in a clinical pharmacology, single-dose, two-treatment, cross-over study and randomised to receive oral doses of Rifaximin polymorph-α and a generic of Rifaximin on the market, after an overnight fast with at least 7 days’ wash-out between sequences. PK assessments were performed evaluating plasma and urine rifaximin levels by liquid chromatography-tandem mass spectrometry on samples collected at the following times: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 and 24 hours post-dosing for blood and 0 (from awakening until drug administration), 0-4, 4-8, 8-12, 12-24, 24-48 hours post-dosing for urine. The systemic absorption of the two rifaximin products was considered equivalent when Cmax, Aeo-t, AUC0-∞ 90% CIs were within the interval 0.80-1.25.
Results: Rifaximin-α and generic Rifaximin PK parameters are reported in the following table with relative 90% CIs.
| Rifaximin |
Geometric mean Rifaximin-α |
Geometric mean generic Rifaximin |
90% CIs |
| Cmax (ng/mL) | 1.97 | 5.98 | 0.2733-0.3963 |
| AUC0-t (ng/mL x h) | 4.86 | 22.51 | 0.1798-0.2593 |
| AUC0-∞ (ng/mL x h) | 7.87 | 26.89 | 0.2477-0.3460 |
| Ae0-48h (µg) | 39.91 | 103.39 | 0.3226-0.4619 |
Conclusions: Generic Rifaximin 200 mg film-coated tablet administered as single oral 400 mg dose to healty volunteers in fasting condition showed higher plasma concentrations when compared to Rifaximin-α 200 mg film-coated tablet, administered at the same dose, leading to plasma concentrations and PK parameters of the active compound 3-4 times higher than dose calculated with Rifaximin-α. These results could be most likely justified by differences in polymorphism of the active ingredient. Different bioavailability could lead to different therapeutic efficacy and safety profile in clinical practice.