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Plazomicin (ACHN490; ACHN-490; Trade name: Zemdri) is a next-generation aminoglycoside antibacterial derived from sisomicin by appending a hydroxy-aminobutyric acid (HABA) substituent at position 1 and a hydroxyethyl substituent at position 6'. In June 2018, Plazomicin gained FDA approval to treat adults with complicated urinary tract infections. Plazomicin has been reported to demonstrate in vitro synergistic activity when combined with daptomycin or ceftobiprole versus methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant S. aureus (VRSA) and against Pseudomonas aeruginosa when combined with cefepime, doripenem, imipenem or piperacillin/tazobactam. It also demonstrates potent in vitro activity versus carbapenem-resistant Acinetobacter baumannii.
Physicochemical Properties
| Molecular Formula | C25H48N6O10 |
| Molecular Weight | 592.69 |
| Exact Mass | 592.343 |
| CAS # | 1154757-24-0 |
| Related CAS # | 1154757-24-0 (free);1380078-95-4 (sulfate); |
| PubChem CID | 42613186 |
| Appearance | Typically exists as solid at room temperature |
| LogP | -6.2 |
| Hydrogen Bond Donor Count | 11 |
| Hydrogen Bond Acceptor Count | 15 |
| Rotatable Bond Count | 13 |
| Heavy Atom Count | 41 |
| Complexity | 873 |
| Defined Atom Stereocenter Count | 12 |
| SMILES | C[C@]1(O)CO[C@H](O[C@H]2[C@H](NC([C@@H](O)CCN)=O)C[C@H](N)[C@@H](O[C@@H]3[C@H](N)CC=C(O3)CNCCO)[C@@H]2O)[C@H](O)[C@H]1NC |
| InChi Key | IYDYFVUFSPQPPV-PEXOCOHZSA-N |
| InChi Code | InChI=1S/C25H48N6O10/c1-25(37)11-38-24(18(35)21(25)29-2)41-20-15(31-22(36)16(33)5-6-26)9-14(28)19(17(20)34)40-23-13(27)4-3-12(39-23)10-30-7-8-32/h3,13-21,23-24,29-30,32-35,37H,4-11,26-28H2,1-2H3,(H,31,36)/t13-,14+,15-,16+,17+,18-,19-,20+,21-,23-,24-,25+/m1/s1 |
| Chemical Name | D-Streptamine, O-2-amino-2,3,4,6-tetradeoxy-6-((2-hydroxyethyl)amino)-alpha-D-glycero- hex-4-enopyranosyl-(1->4)-O-(3-deoxy-4-C-methyl-3-(methylamino)-beta-L- arabinopyranosyl-(1->6))-N(sup 1)-((2S)-4-amino-2-hydroxy-1-oxobutyl)-2-deoxy- |
| Synonyms | ACHN490; ACHN-490; Trade name: Zemdri |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Administration of 15 mg/kg plazomicin by 30-minute IV infusion resulted in peak plasma concentrations of 73.7 ± 19.7 μg/mL in healthy adult subjects and 51.0 ± 26.7 μg/mL in patients with complicated urinary tract infections (cUTI). The area under the curve (AUC) were 257 ± 67.0 μg.h/mL in healthy adults and 226 ± 113 μg.h/mL in cUTI patients. Plazomicin predominantly undergoes renal excretion, where 56% of the total administered drug was recovered in the urine within 4 hours following a single 15 mg/kg IV dose of radiolabeled plazomicin in healthy subjects. About less than 0.2% and 89.1% of the total drug were recovered within 168 hours in feces and urine, respectively. The mean (±SD) volume of distribution is 17.9 (±4.8) L in healthy adults and 30.8 (±12.1) L in cUTI patients. Following administration of 15 mg/kg plazomicin by 30-minute IV infusion, the mean (±SD) total body clearance in healthy adults and cUTI patients is 4.5 (±0.9) and 5.1 (±2.01) L/h, respectively. Metabolism / Metabolites Plazomicin is not reported to undergo significant metabolism. Biological Half-Life The mean (±SD) half-life of plazomicin was 3.5 h (±0.5) in healthy adults with normal renal function receiving 15 mg/kg plazomicin via intravenous infusion. |
| Toxicity/Toxicokinetics |
Hepatotoxicity Intravenous therapy with plazomicin has been linked to only rare instances of serum enzyme elevations ( Likelihood score: E (unlikely cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Plazomicin is an aminoglycoside antibiotic similar to gentamicin and amikacin. No information is available on the use of plazomicin during breastfeeding. However, based on the excretion of other aminoglycoside antibiotics, amounts in milk are expected to be low. Monitor the infant for possible effects on the gastrointestinal flora, such as diarrhea, candidiasis (e.g., thrush, diaper rash) or rarely, blood in the stool indicating possible antibiotic-associated colitis. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding The extent of plasma protein binding in humans is approximately 20%. The degree of protein binding was concentration-independent across the range tested in vitro (5 to 100 mcg/mL). |
| References | :Antimicrob Agents Chemother.2010 Nov;54(11):4636-42;Antimicrob Agents Chemother.2015 Oct;59(10):5959-66. |
| Additional Infomation |
Developed by Achaogen biopharmaceuticals, plazomicin is a next-generation aminoglycoside synthetically derived from [DB12604]. The structure of plazomicin was established via appending hydroxylaminobutyric acid to [DB12604] at position 1 and 2-hydroxyethyl group at position 6'. It was designed to evade all clinically relevant aminoglycoside-modifying enzymes, which contribute to the main resistance mechanism for aminoglycoside therapy. However, acquired resistance of aminoglycosides may arise through over expression of efflux pumps and ribosomal modification by bacteria, which results from amino acid or rRNA sequence mutations. Like other aminoglycosides, plazomicin is ineffective against bacterial isolates that produce 16S rRNA methyltransferases. Plazomicin mediates the antibacterial activity against pathogens including carbapenem-resistant (CRE) and extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae. It mediates the antibacterial activity by binding to bacterial 30S ribosomal subunit and inhibiting protein synthesis. On June 28th, 2018, plazomicin sulfate was approved by the FDA for use in adult patients for the treatment of complicated urinary tract infections (cUTI) including Pyelonephritis. It is marketed as Zemdri and is administered via once-daily intravenous infusion. Plazomicin is a parenterally administered, broad spectrum aminoglycoside antibiotic typically used for moderate-to-severe urinary tract infections or pyelonephritis. Plazomicin has had limited clinical use but has not been linked to serum enzyme elevations during therapy or to instances of clinically apparent liver injury. See also: Plazomicin Sulfate (is active moiety of). Drug Indication Plazomicin is indicated for the treatment of patients 18 years of age or older with Complicated Urinary Tract Infections (cUTI) including Pyelonephritis, who have limited or no alternative treatment options. It should only be used to treat infections that are proven or strongly suspected to be caused by susceptible microorganisms. FDA Label Mechanism of Action Plazomicin exerts a bactericidal action against susceptible bacteria by binding to bacterial 30S ribosomal subunit. Aminoglycosides typically bind to the ribosomal aminoacyl-tRNA site (A-site) and induce a conformational change to further facilitate the binding between the rRNA and the antibiotic. This leads to codon misreading and mistranslation of mRNA during bacterial protein synthesis. Plazomicin demonstrates potency against _Enterobacteriaceae_, including species with multidrug-resistant phenotypes such as carbapenemase-producing bacteria and isolates with resistance to all other aminoglycosides. Its antibacterial activity is not inhibited by aminoglycoside modifying enzymes (AMEs) produced by bacteria, such as acetyltransferases (AACs), phosphotransferases (APHs), and nucleotidyltransferases (ANTs). Plazomicin was shown to be effective against _Enterobacteriaceae_ in presence of some beta-lactamases. In clinical settings and _in vivo_, bacteria shown to be susceptible toward plazomicin include _Escherichia_ _coli_, _Klebsiella pneumoniae_, _Proteus mirabilis_, and _Enterobacter cloacae_. Other aerobic bacteria that may be affected by plazomicin are _Citrobacter freundii_, _Citrobacter koseri_, _Enterobacter aerogenes_, _Klebsiella oxytoca_, _Morganella morganii_, _Proteus vulgaris_, _Providencia stuartii_, and _Serratia marcescens_. Pharmacodynamics Plazomicin exerts its antibacterial activity in a dose-dependent manner with a post-antibiotic effect ranging from 0.2 to 2.6 hours at 2X MIC against _Enterobacteriaceae_, as demonstrated by _in vitro_ studies. In clinical trials comprising of hospitalized adult patients with cUTI (including pyelonephritis), resolution or improvement of clinical cUTI symptoms and a microbiological outcome of eradication were observed at day 5 following the first dose administration of plazomicin. Plazomicin has shown to elicit nephrotoxic, ototoxic, and neuromuscular blocking effects. In clinical trials, it did not induce any clinically relevant QTc-prolonging effects. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6872 mL | 8.4361 mL | 16.8722 mL | |
| 5 mM | 0.3374 mL | 1.6872 mL | 3.3744 mL | |
| 10 mM | 0.1687 mL | 0.8436 mL | 1.6872 mL |