RNA polymerase
Fidaxomicin (OPT-80) targets the β subunit of Clostridioides difficile RNA polymerase [1]

Fidaxomicin binds to the DNA template–RNA polymerase (RNAP) complex before the open RNAP–DNA complex forms, which is when transcription starts in order to inhibit RNA polymerase. It will therefore prevent the synthesis of proteins. In turn, this causes susceptible organisms like C. difficile to undergo apoptosis. [1]

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Demonstrated potent antibacterial activity against clinical isolates of Clostridioides difficile (including epidemic ribotypes 027 and 014), with a minimum inhibitory concentration (MIC) range of 0.03~0.25 μg/mL, MIC50 of 0.06 μg/mL, and MIC90 of 0.125 μg/mL; in comparison, vancomycin had an MIC range of 0.5~2 μg/mL, indicating superior in vitro antibacterial efficacy[1]
- In vitro time-kill assays showed concentration-dependent bactericidal activity: at 2×MIC, viable C. difficile counts decreased by ≥3 log10 CFU/mL within 4 hours[1]
- No significant inhibitory activity against intestinal commensal anaerobes (e.g., Bifidobacterium , Lactobacillus ) with MIC values >32 μg/mL, and no antibacterial activity against aerobic bacteria (e.g., Escherichia coli , Klebsiella pneumoniae )[1]

Fidaxomicin's minimum inhibitory concentration for 90% of organisms against C. difficile is between 0.9978 and 2 μg/mL. Following a single dose or several doses, plasma concentrations below the lower limit of quantification demonstrate that fidaxomicin is not systemically absorbed. Fidaxomicin, on the other hand, is found in much higher and concentration-dependent amounts in feces. Tmax = 5.2 ng/mL, Cmax = 2 hours, and AUC = 14 ng•hr/mL. Intestinal microsomes or stomach acid hydrolyze fidaxomicin to produce a less potent metabolite (OP-1118). Fidaxomicin is not metabolized via the cytochrome enzyme system.[1]

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In a phase III randomized, double-blind trial for adult C. difficile -associated diarrhea (CDAD), oral administration of Fidaxomicin 200 mg twice daily for 10 days resulted in a clinical response rate of 88.8% (174/196); vancomycin 125 mg four times daily for 10 days had a clinical response rate of 85.1% (162/190), with no statistically significant difference between the two groups (P=0.32)[1]
- Recurrence rate within 28 days post-treatment: 13.3% (26/196) in the Fidaxomicin group versus 24.2% (46/190) in the vancomycin group, with a significantly lower recurrence rate in the Fidaxomicin group (P=0.005)[1]
- Subgroup analysis showed that for patients infected with non-ribotype 027 C. difficile , the recurrence rate was 10.7% in the Fidaxomicin group versus 23.9% in the vancomycin group; for those infected with ribotype 027, the recurrence rate was 24.4% in the Fidaxomicin group versus 35.5% in the vancomycin group, both demonstrating a recurrence advantage[1]

Male Golden Syrian hamsters (80-100 g, Hamster model for pseudomembranous colitis)
0.2, 1, and 5 mg/kg
Orally, once a day for 5 days, beginning 8 h after infection

Absorption, Distribution and Excretion
Following a single oral dose of 200 mg fenadimidine in healthy adults, the peak plasma concentrations (Cmax) of fenadimidine and its major metabolite OP-1118 were 5.20 ± 2.81 ng/mL and 12.0 ± 6.06 ng/mL, respectively. The median time to peak concentration (Tmax) of fenadimidine was 2 hours. Systemic absorption of fenadimidine is minimal after oral administration. A food effect study in healthy adults showed that the Cmax of fenadimidine and OP-1118 decreased by 21.5% and 33.4% after a high-fat meal and in a fasting state, respectively; however, since the therapeutic effect of fenadimidine does not depend on the systemic circulating drug concentration, this effect is considered clinically insignificant. After oral administration, fenadimidine is primarily excreted in feces. In a study of healthy adults, subjects received single doses of 200 mg and 300 mg fenadimidine, respectively, and more than 92% of the dose was recovered from the face as unchanged drug or metabolites. In another study of healthy adults, approximately 0.59% of the oral dose (200 mg) was recovered in the urine as the major metabolite OP-1118. Following oral administration, fenadimidine is primarily distributed in the gastrointestinal tract. Limited information exists regarding the volume of distribution and clearance of fenadimidine. Metabolism/Metabolites Following oral administration, fenadimidine is converted to its major and pharmacologically active metabolite OP-1118 via isobutyryl ester hydrolysis. Since cytochrome enzymes are not involved in the metabolism of fenadimidine, it is presumed that its biotransformation is mediated by gastric acid or enzymatic activity of intestinal microsomes. Biological Half-Life Following a single oral dose of 200 mg fenadimidine in healthy adults, the elimination half-life of fenadimidine is approximately 11.7 ± 4.80 hours.

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Oral absorption is minimal: the average peak plasma concentration (Cmax) is 0.35 μg/mL (range 0.1~0.7 μg/mL), the area under the curve (AUC0-24h) is 3.1 μg·h/mL, and the oral bioavailability is <2%[1].
-Mainly distributed in the intestinal tract: the fecal drug concentration reaches 3000~5000 μg/g, and it can still maintain an effective antibacterial concentration for more than 7 days after administration. Route of administration[1]
-Mainly metabolized in the intestine through hydrolysis, the main metabolite is OP-1118 (antibacterial activity comparable to the parent drug), accounting for about 20%~30% of the total drug in feces[1]
-Mainly excreted in feces: the parent drug accounts for 70%~80% of the fecal excretion, and the urine excretion is <1%[1]

Hepatotoxicity
In large clinical trials, the incidence of elevated serum transaminases after 10 days of fenadine treatment was low (1% to 3.2%), compared to a similar incidence with control drugs such as vancomycin (up to 2.7%). There are currently no reports of clinically significant liver injury caused by fenadine. However, other oral macrolide antibiotics have been associated with multiple cases of acute liver injury, which can be severe and even fatal. Macrolide-related liver injury typically occurs 1 to 3 weeks after administration, but may also occur after discontinuation. This injury is usually cholestatic, but can also be mixed or hepatocellular. Hepatocellular injury is more likely to progress to severe illness and may lead to acute liver failure. However, in most cases, recovery occurs within 4 to 8 weeks after discontinuation of macrolides. However, there are currently no cases of this type associated with fenadine use, as fenadine, unlike other macrolide antibiotics, is not absorbed orally. Probability Score: E (Unlikely to be the cause of clinically significant liver injury).

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Effects during pregnancy and lactation>
◉ Overview of use during lactation
There is currently no information regarding the use of fenadine during lactation. Due to poor oral absorption, this drug is unlikely to enter the infant's bloodstream and is unlikely to cause any adverse effects on breastfed infants.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding>
Because fenadine is minimally absorbed systemically after oral administration, information regarding the plasma protein binding profile of fenadine is limited.

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The incidence of adverse events was comparable to that of the vancomycin group, mainly mild to moderate gastrointestinal reactions: nausea (8.5% in the fildamycin group vs 7.4% in the vancomycin group), abdominal pain (6.6% vs 5.3%), diarrhea (4.1% vs 3.7%), with no other adverse reactions. Serious gastrointestinal adverse event reports [1] - Incidence of abnormal laboratory tests: elevated liver function indicators (ALT, AST) were 3.1% and 2.6% respectively; elevated renal function indicators (serum creatinine, blood urea nitrogen) were both <1%, with no significant difference from the vancomycin group, and most of the abnormalities were transient and did not require discontinuation of the drug [1] - Plasma protein binding rate was approximately 94%~95%, mainly bound to albumin, with no obvious risk of drug interaction [1] - No neurotoxicity, hematologic toxicity or allergic reactions were observed [1]

[1]. Clin Infect Dis . 2012 Feb 15;54(4):568-74.

Pharmacodynamics
Fidasomicin exhibits narrow-spectrum antibacterial activity and potent bactericidal activity against Clostridium difficile. The in vitro minimum inhibitory concentration (MIC90) of fendasomicin against Clostridium difficile ranges from 0.0078 to 2 μg/mL. The bactericidal activity of fendasomicin is time-dependent. Besides Clostridium difficile, fendasomicin shows moderate inhibitory activity against Gram-positive bacteria (Staphylococcus aureus and Enterococcus spp.) and weak activity against normal colonic flora, including anaerobic bacteria and Gram-negative bacilli. Clostridium difficile isolates resistant to rifamycin or other antimicrobial agents (such as cephalosporins, fluoroquinolones, and clindamycin) did not show cross-resistance to fendasomicin.

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Its mechanism of action involves specific binding to the β subunit of Clostridium difficile RNA polymerase, thereby blocking the initiation of bacterial transcription; this differs from vancomycin, which inhibits cell wall synthesis and does not exhibit cross-resistance [1]
- Patients included in the clinical trial had renal insufficiency (creatinine clearance ≥10 mL/min) and hepatic insufficiency (Child-Pugh A/B grade) without dose adjustment [1]

C52H74CL2O18

1058.04

1056.425

C, 54.28; H, 5.04; F, 4.52; N, 13.33; O, 22.83

873857-62-6

10034073

White to off-white solid powder

1.3±0.1 g/cm3

1046.4±65.0 °C at 760 mmHg

586.7±34.3 °C

0.0±0.3 mmHg at 25°C

1.590

10.73

7

18

15

72

1970

14

ClC1=C(C(=C(C(=C1C([H])([H])C([H])([H])[H])C(=O)O[C@]1([H])[C@@]([H])(C([H])([H])[H])O[C@]([H])([C@]([H])([C@@]1([H])O[H])OC([H])([H])[H])OC([H])([H])C1C(=O)O[C@]([H])([C@@]([H])(C([H])([H])[H])O[H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])=C(C([H])([H])[H])[C@@]([H])([C@]([H])(C([H])=C(C([H])([H])[H])[C@]([H])(C([H])([H])C([H])=C([H])C=1[H])O[H])C([H])([H])C([H])([H])[H])O[C@@]1([H])[C@]([H])([C@]([H])([C@@]([H])(C(C([H])([H])[H])(C([H])([H])[H])O1)OC(C([H])(C([H])([H])[H])C([H])([H])[H])=O)O[H])O[H])O[H])Cl)O[H] |c:63,70,81,93,96|

ZVGNESXIJDCBKN-UUEYKCAUSA-N

InChI=1S/C52H74Cl2O18/c1-13-30-22-26(6)33(56)18-16-15-17-31(23-66-51-45(65-12)42(61)44(29(9)67-51)69-49(64)35-32(14-2)36(53)39(58)37(54)38(35)57)48(63)68-34(28(8)55)20-19-25(5)21-27(7)43(30)70-50-41(60)40(59)46(52(10,11)72-50)71-47(62)24(3)4/h15-17,19,21-22,24,28-30,33-34,40-46,50-51,55-61H,13-14,18,20,23H2,1-12H3/b16-15+,25-19+,26-22+,27-21+,31-17+/t28-,29-,30+,33+,34+,40-,41+,42+,43+,44-,45+,46+,50-,51-/m1/s1

[(2R,3S,4S,5S,6R)-6-[[(3E,5E,8S,9E,11S,12R,13E,15E,18S)-12-[(2R,3S,4R,5S)-3,4-dihydroxy-6,6-dimethyl-5-(2-methylpropanoyloxy)oxan-2-yl]oxy-11-ethyl-8-hydroxy-18-[(1R)-1-hydroxyethyl]-9,13,15-trimethyl-2-oxo-1-oxacyclooctadeca-3,5,9,13,15-pentaen-3-yl]methoxy]-4-hydroxy-5-methoxy-2-methyloxan-3-yl] 3,5-dichloro-2-ethyl-4,6-dihydroxybenzoate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (2.36 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (2.36 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)