Systemic Absorption of Rifamycin SV MMX Administered as Modified-Release Tablets in Healthy Volunteers

Stefano, Andrea F. D. Di; Rusca, Antonio; Loprete, Luca; Dröge, Melloney J.; Moro, Luigi; Assandri, Alessandro

doi:10.1128/aac.01504-10

Cited by 20 publications

(17 citation statements)

References 14 publications

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“…In a pharmacokinetic study in healthy volunteers, RIF-MMX was well tolerated and plasma concentrations indicated minimal (<1%) systemic bioavailability. 8 The antimicrobial activity of rifamycin SV is thought to be predominantly through interference with DNA-dependent RNA polymerase. 9 In vitro, rifamycin SV is effective against the bacterial pathogens which most frequently cause TD and against Clostridium difficile.…”

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confidence: 99%

Targeting of Rifamycin SV to the Colon for Treatment of Travelers' Diarrhea: A Randomized, Double‐Blind, Placebo‐Controlled Phase 3 Study

DuPont¹,

Petersen²,

Zhao

et al. 2014

J Travel Med

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Background. Rifamycin SV is under development for treatment of travelers' diarrhea (TD) in a new oral formulation, Rifamycin SV MMX ® (RIF-MMX; Santarus Inc., San Diego, CA, USA), which targets its delivery to the colon, making it a unique rifamycin drug. Methods. This was a randomized, double-blind, phase 3 study of adult travelers to Mexico or Guatemala experiencing acute diarrhea. A total of 264 patients received RIF-MMX (2 × 200 mg twice daily for 3 days, n = 199) or placebo (n = 65) in a 3 : 1 ratio. The primary endpoint was the length of time between the administration of first dose of study drug and passage of the last unformed stool (TLUS; after which clinical cure was declared). Other endpoints included eradication of pathogens from the stools, pathogen minimum inhibitory concentration (MIC), and adverse events (AEs). Results. TLUS was significantly shorter in the RIF-MMX group (median: 46.0 hours) compared with placebo (median: 68.0 hours; p = 0.0008) and a larger percentage of RIF-MMX treated patients (81.4%) achieved clinical cure compared with placebo patients (56.9%). TLUS was significantly shorter in the subgroups of patients with enteroaggregative, enterotoxigenic, or diffusely adherent Escherichia coli infections (p = 0.0035) with nonsignificant activity against invasive bacteria (p = 0.3804). Overall pathogen eradication rates were numerically higher in the RIF-MMX group (67.0%) compared with placebo (54.8%) but the difference did not reach significance (p = 0.0836). In vitro resistance to rifamycin SV was observed in some bacteria remaining after treatment of patients with RIF-MMX but was not associated with lower efficacy in them. AEs appeared to be more frequent with placebo (38.5%) than with RIF-MMX (29.6%). Conclusions. RIF-MMX shortened the duration of TD in patients with a broad range of pathogens and was well tolerated. The unique pharmacokinetic properties of the drug offer evidence that TD pathogens work at the level of the colon.

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confidence: 99%

Targeting of Rifamycin SV to the Colon for Treatment of Travelers' Diarrhea: A Randomized, Double‐Blind, Placebo‐Controlled Phase 3 Study

DuPont¹,

Petersen²,

Zhao

et al. 2014

J Travel Med

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“…However, the increased MICs for Rifamycin are still largely below the high intraluminal and faecal concentrations of RIF-MMX. 20 Also, the high MICs for Campylobacter have to be seen in this context. In contrast, fluoroquinolone resistance has expanded from Campylobacter-associated cases in Southeast Asia to widespread occurrence, and increases among other common bacterial enteropathogens including ETEC, EAEC, Shigella and non-typhoidal Salmonella .…”

Section: Discussionmentioning

confidence: 99%

“…19 In humans, Rifamycin SV <1% of the administered dose is absorbed after oral administration of RIF-MMX. 20…”

Section: Introductionmentioning

confidence: 99%

Rifamycin SV-MMX® for treatment of travellers’ diarrhea: equally effective as ciprofloxacin and not associated with the acquisition of multi-drug resistant bacteria

Steffen

Jiang

Garcia³

et al. 2018

Journal of Travel Medicine

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BackgroundThe novel oral antibiotic formulation Rifamycin SV-MMX®, with a targeted delivery to the distal small bowel and colon, was superior to placebo in treating travellers’ diarrhea (TD) in a previous study. Thus, a study was designed to compare this poorly absorbed antibiotic with the systemic agent ciprofloxacin.MethodsIn a randomized double-blind phase 3 study (ERASE), the efficacy and safety of Rifamycin SV-MMX® 400 mg twice daily (RIF-MMX) was compared with ciprofloxacin 500 mg twice daily in the oral treatment of TD. Overall, 835 international visitors to India, Guatemala or Ecuador with acute TD were randomized to receive a 3-day treatment with RIF-MMX (n = 420) or ciprofloxacin (n = 415). Primary endpoint was time to last unformed stool (TLUS), after which clinical cure was declared. Stools samples for microbiological evaluation were collected at the baseline visit and the end of treatment visit.ResultsMedian TLUS in the RIF-MMX group was 42.8 h versus 36.8 h in the ciprofloxacin group indicating non-inferiority of RIF-MMX to ciprofloxacin (P = 0.0035). Secondary efficacy endpoint results including clinical cure rate, treatment failure rate, requirement of rescue therapy as well as microbiological eradication rate confirmed those of the primary analysis indicating equal efficacy for both compounds. While patients receiving ciprofloxacin showed a significant increase of Extended Spectrum Beta Lactamase Producing—Escherichia coli (ESBL-E. Coli) colonization rates after 3-days treatment (6.9%), rates did not increase in patients receiving RIF-MMX (−0.3%). Both drugs were well-tolerated and safe.ConclusionThe novel multi-matrix formulation of the broad-spectrum, poorly absorbed antibiotic Rifamycin SV was found non-inferior to the systemic antibiotic ciprofloxacin in the oral treatment of non-dysenteric TD with the advantage of a lower risk of ESBL-E. Coli acquisition.

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“…In addition, the pharmacokinetics of rifamycin SV was previously investigated in healthy male and female subjects after single and multiple administrations of the 200 mg tablets [8]. Oral rifamycin SV was confirmed to have a negligible oral systemic bioavailability, further reduced by the MMX formulation that focuses the drug release in the colon lumen.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Safety of Rifamycin SV after Single and Multiple Doses of MMX® Modified Release Tablets in Healthy Male and Female Volunteers

Stefano¹,

Radicioni²,

Vaccani³

et al. 2021

Antibiotics

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The primary objective of this single- and multiple-dose pharmacokinetic study was the investigation of rifamycin SV’s pharmacokinetic profile in plasma and urine. All the 18 enrolled healthy men and post-menopausal women received modified release tablets containing 600 mg of the oral non-absorbable antibiotic, rifamycin SV, according to a multiple dose regimen: one tablet three times a day (daily intake: 1800 mg) for 14 consecutive days. Blood sampling and urine collection were performed up to 24 h post-dose after the first dose on Days 1 and 7. On average, on Day 1, Cmax,0–24 was 5.79 ± 4.24 ng/mL and was attained in a median time of 9 h. On Day 7, all the subjects had quantifiable levels of rifamycin SV in plasma at each sampling time. After a peak concentration attained 2 h post-dose (mean ± SD concentration: 10.94 ± 16.41 ng/mL), rifamycin SV decreased in plasma to levels similar to those of Day 1. The amounts of rifamycin SV excreted in urine paralleled the plasma concentration at the corresponding times. On Day 1, the total amount excreted in urine was 0.0013%, and was 0.0029% on Day 7. The study results confirmed those of the previous Phase I study: the systemic absorption of rifamycin SV was also proved negligible after 7 days of the 600 mg t.i.d. dose regimen of the newly formulated tablets, currently under development for the treatment of several small and large intestinal pathologies, including diarrhea-predominant irritable bowel syndrome, hepatic encephalopathy, and others. Registered at ClinicalTrials.gov with the identifier NCT02969252, last updated on 26JAN18.

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Systemic Absorption of Rifamycin SV MMX Administered as Modified-Release Tablets in Healthy Volunteers

Cited by 20 publications

References 14 publications

Targeting of Rifamycin SV to the Colon for Treatment of Travelers' Diarrhea: A Randomized, Double‐Blind, Placebo‐Controlled Phase 3 Study

Targeting of Rifamycin SV to the Colon for Treatment of Travelers' Diarrhea: A Randomized, Double‐Blind, Placebo‐Controlled Phase 3 Study

Rifamycin SV-MMX® for treatment of travellers’ diarrhea: equally effective as ciprofloxacin and not associated with the acquisition of multi-drug resistant bacteria

Pharmacokinetics and Safety of Rifamycin SV after Single and Multiple Doses of MMX® Modified Release Tablets in Healthy Male and Female Volunteers

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