Plazomicin

Plazomicin belongs to the pharmacological class of Aminoglycoside antibiotics.

Plazomicin has been approved to relieve symptoms and also for the treatment and maintenance of Plague, Urinary tract infections.

Plazomicin, administered at a dose of 15 mg/kg via a 30-minute intravenous infusion, resulted in peak plasma concentrations of 73.7 ± 19.7 μg/mL in healthy adults and 51.0 ± 26.7 μg/mL in patients with complicated urinary tract infections (cUTI). The area under the curve (AUC) was 257 ± 67.0 μg.h/mL in healthy adults and 226 ± 113 μg.h/mL in cUTI patients. The volume of distribution was approximately 17.9 L in healthy adults and 30.8 L in cUTI patients. Plazomicin exhibits approximately 20% plasma protein binding, which is concentration-independent across the tested range. It undergoes minimal metabolism and is primarily eliminated via renal excretion, with 56% recovered in urine within 4 hours following administration. Less than 0.2% and 89.1% of the total drug were recovered in feces and urine, respectively, within 168 hours.

The common side effects involved in using Plazomicin are Hematuria, Urinary frequency or volume changes, Respiratory difficulty, Somnolence, Polydipsia, Anorexia, Nausea, Edema, Emesis.

Plazomicin is available in the form of Injectables.

Plazomicin is approved in Germany, Japan, Malaysia, India, the U.K., the U.S, and China.

Plazomicin belongs to the pharmacological class of Aminoglycoside antibiotics.

Plazomicin acts as a bactericidal agent against bacteria that are susceptible to its effects. It achieves this by binding to the 30S ribosomal subunit of the bacteria. Aminoglycosides, including plazomicin, typically bind to the aminoacyl-tRNA site (A-site) on the ribosome. This binding triggers a conformational change that enhances the interaction between the ribosomal RNA (rRNA) and the antibiotic. As a result, there is a disruption in the accurate reading of codons and the translation of mRNA during the bacterial protein synthesis process. This mechanism ultimately contributes to the bactericidal activity of plazomicin.

Plazomicin has been approved to relieve symptoms and also for the treatment and maintenance of Plague, Urinary tract infections.

For healthy subjects, the geometric mean (± standard deviation) values for the area under the concentration-time curve (AUC) were 257 (±67.0) mcg·h/mL, the maximum concentration (Cmax) was 73.7 (±19.7) mcg/mL, and the minimum concentration (Cmin) was 0.3 (±0.2) mcg/mL. These values were determined in a study involving 54 participants.

In the case of patients with complicated urinary tract infections (cUTI), the geometric mean (± standard deviation) values for AUC were 226 (±113) mcg·h/mL, Cmax was 51.0 (±26.7) mcg/mL, and Cmin was 0.5 (±1.2) mcg/mL. This data was obtained from a study involving 87 participants.

Plazomicin is found to be available in the form of Injectables.

Plazomicin can be used in the following treatment:

● Plague

● Urinary tract infections

Plazomicin can help to relieve symptoms and also for the treatment and maintenance of Plague Urinary tract infections.

Plazomicin is approved for use in the following clinical indications:

● Plague

● Urinary tract infections

● Plague:

For the treatment of plague caused by Y. pestis as an alternative agent (off-label use), it is recommended to consult public health officials for event-specific recommendations. The recommended dosage of Plazomicin is 15 mg/kg administered intravenously once daily for 7 to 14 days. Treatment should continue for at least a few days after clinical resolution.

● Complicated Urinary Tract Infection:

For complicated urinary tract infections, including pyelonephritis or urinary tract infections with systemic signs/symptoms, Plazomicin can be considered as an alternative agent. It is important to reserve its use for patients with or at risk for resistant infections, such as carbapenem-resistant Enterobacterales. In inpatients, the recommended dosage is 15 mg/kg administered intravenously once daily. Once symptoms improve, if culture and susceptibility results allow, patients can be switched to an appropriate oral regimen. The total duration of therapy can range from 5 to 14 days, depending on the clinical response and the chosen antimicrobial agent to complete the treatment.

For outpatients, the recommended dosage is an initial intravenous dose of 15 mg/kg, followed by 5 to 14 days of appropriate oral therapy.It is worth noting that for patients who are systemically ill, at risk for more severe illness, or at risk for multidrug-resistant infection, some experts may continue daily parenteral therapy until culture and susceptibility testing results are available.

Dosage Adjustments in Kidney Patients:

● For patients with a creatinine clearance (CrCl) of 60 to 90 mL/min, the recommended dosage is 15 mg/kg administered intravenously once every 24 hours.

● For patients with a CrCl of 30 to 60 mL/min, the recommended dosage is 10 mg/kg administered intravenously once every 24 hours.

● For patients with a CrCl of 15 to 30 mL/min, the recommended dosage is 10 mg/kg administered intravenously once every 48 hours.

● For patients with a CrCl less than 15 mL/min, those requiring hemodialysis, or those receiving continuous renal replacement therapy, there is insufficient information available to provide specific dosage recommendations.

Dosage Adjustments in Hepatic Impairment Patients:

No dosage adjustments are needed for hepatic impairment.

Dosage Adjustments in Pediatric Patients:

● Safety and efficacy of Plazomicin have not been established in individuals younger than 18 years of age.

Injectables : 500mg/10mL (50mg/mL)

Injectables

There are no specific dietary restrictions related to the use of Plazomicin. However, it is generally recommended to follow a balanced and healthy diet while undergoing treatment with any medication, including Plazomicin. Eating a nutritious diet can support overall health and aid in the recovery process.

It is important to maintain adequate hydration during treatment with Plazomicin and in general. Drinking an adequate amount of water and fluids can help support kidney function and prevent dehydration.

Plazomicin may be contraindicated under the following conditions:

Patients with a known allergy to Plazomicin or any of its components should avoid using Plazomicin Sulfate Injection USP. Additionally, if a patient has a history of hypersensitivity or serious toxic reactions to aminoglycosides, it may also be contraindicated to use any other aminoglycoside due to the possibility of cross-sensitivities that can occur within this class of drugs.

● Nephrotoxicity, characterized by potential kidney damage, has been reported with the use of Plazomicin. Most cases of increased serum creatinine levels were reversible and remained within 1 mg/dL above the baseline. In a clinical trial, the incidence of adverse reactions related to renal function was higher in Plazomicin-treated patients compared to those treated with meropenem. Serum creatinine increases of 0.5 mg/dL or more above baseline were observed more frequently in Plazomicin-treated patients with lower kidney function and higher plazomicin levels. It is recommended to assess kidney function before and during Plazomicin therapy, particularly in patients at risk of nephrotoxicity, such as those with renal impairment or receiving other nephrotoxic medications.

● Ototoxicity, characterized by hearing loss, tinnitus, and vertigo, has also been reported with Plazomicin use. These symptoms may be irreversible and can appear even after completion of therapy. In clinical trials, there were isolated cases of reversible hypoacusis and tinnitus in Plazomicin-treated patients, as well as cases of irreversible tinnitus, reversible vertigo, and abnormal audiogram in both Plazomicin and comparator groups. Patients with a family history of hearing loss, renal impairment, or who receive higher doses or longer treatment durations may be at greater risk. The potential benefit-risk of Plazomicin treatment should be carefully considered in these patients.

● Plazomicin may exacerbate muscle weakness in patients with underlying neuromuscular disorders or delay the recovery of neuromuscular function in patients receiving neuromuscular blocking agents. Close monitoring for adverse reactions related to neuromuscular blockade is advised, especially in high-risk patients such as those with neuromuscular disorders or those receiving concurrent neuromuscular blocking agents.

● The use of Plazomicin during pregnancy can potentially cause fetal harm. Aminoglycosides, including Plazomicin, can cross the placenta, and previous reports have linked streptomycin (an aminoglycoside) to irreversible congenital deafness in infants exposed in utero. Pregnant women or those who become pregnant while taking Plazomicin should be informed about the potential risk to the fetus.

● Hypersensitivity reactions, including serious and occasionally fatal anaphylactic reactions, have been reported in patients receiving aminoglycoside drugs. Prior to initiating Plazomicin therapy, it is important to inquire about any previous hypersensitivity reactions to aminoglycosides, as cross-sensitivity may exist among these drugs. Plazomicin should be discontinued if an allergic reaction occurs.

● The use of Plazomicin, like other antibacterial drugs, may lead to Clostridium difficile-associated diarrhea (CDAD). CDAD ranges in severity from mild diarrhea to life-threatening colitis. Alteration of the normal colon flora due to antibacterial treatment can allow for the overgrowth of C. difficile. Prompt evaluation and management are necessary if CDAD is suspected or confirmed, including discontinuation of antibacterial drugs not effective against C. difficile, appropriate fluid and electrolyte management, protein supplementation, and consideration of surgical evaluation when indicated.

● Prescribing Plazomicin in the absence of a proven or strongly suspected bacterial infection is not recommended as it is unlikely to provide benefit to the patient and increases the risk of developing drug-resistant bacteria.

There is no specific alcohol warning for Plazomicin. However, it is generally advisable to avoid consuming alcohol while undergoing treatment with any medication, including Plazomicin. Alcohol can have various effects on the body and may interact with medications, potentially leading to adverse reactions or reducing the effectiveness of the treatment.

Additionally, alcohol can strain the liver and kidneys, which are organs involved in the elimination of medications from the body. Since Plazomicin can have potential side effects on these organs, alcohol consumption may exacerbate these effects.

There is limited information regarding the presence of Plazomicin in human milk and its potential effects on breastfed infants or milk production. Studies conducted in rats have shown the detection of plazomicin in rat milk, albeit at low concentrations (refer to Data). It is important to consider the developmental and health benefits of breastfeeding, alongside the clinical need for Plazomicin in the mother and any potential risks to the breastfed infant arising from Plazomicin or the underlying maternal condition.

Pregnancy Category D:

The administration of aminoglycosides, including Plazomicin, to pregnant women can result in fetal harm. However, there is insufficient data available to determine the specific risk of adverse developmental outcomes associated with Plazomicin use during pregnancy. Published reports on streptomycin, another aminoglycoside, have indicated the potential for irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Animal studies conducted with plazomicin, the active ingredient in Plazomicin, did not show any drug-related visceral or skeletal malformations in pregnant rats and rabbits when administered during organogenesis at doses equivalent to or higher than the clinical dose. However, auditory function of offspring was not evaluated in these animal studies (refer to Data). Pregnant women should be informed of the potential risk to the fetus.

The background risk of major birth defects and miscarriage in the general population is unknown for the indicated patient population. In the general population of the United States, the estimated background risk of major birth defects is 2% to 4%, and the estimated background risk of miscarriage in clinically recognized pregnancies is 15% to 20%.

There are no specific food warnings related to the use of Plazomicin. However, it is generally recommended to follow a balanced and healthy diet while undergoing treatment with any medication, including Plazomicin. Eating a nutritious diet can support overall health and aid in the recovery process.

The adverse reactions related to Plazomicin can be categorized as follows:

Common :

● Hematuria

● Urinary frequency or volume changes

● Respiratory difficulty

● Somnolence

● Polydipsia

● Anorexia

● Nausea

● Edema

● Emesis

Less Common :

● Visual impairment

● Turbid urine

● Disorientation

● Impaired urine concentration

● Loose stools

● Vertigo

● Orthostatic hypotension

● Ear pressure

● Cephalalgia

● Instability

● Hearing loss

● Anxiety

● Tinnitus

● Cardiac arrhythmia

● Auditory impairment

● Fatigue

Rare :

● Gastric burning

● Chest discomfort

● Xerostomia

● Dyspepsia

● Cardiac arrhythmia

● Emotional fluctuations

● Myalgia or cramping

● Paresthesia

● Convulsions

● Gastrointestinal discomfort

● Abdominal tenderness

No significant drug interactions have been found. The risk of nephrotoxicity is increased in patients who are also taking other nephrotoxic medications.

The following are the side effects involving Plazomicin:

● Hematuria

● Urinary frequency or volume changes

● Respiratory difficulty

● Somnolence

● Polydipsia

● Anorexia

● Nausea

● Edema

● Emesis

Pregnancy:

Pregnancy Category D:

Risk Summary:

The administration of aminoglycosides, including Plazomicin, to pregnant women can result in fetal harm. However, there is insufficient data available to determine the specific risk of adverse developmental outcomes associated with Plazomicin use during pregnancy. Published reports on streptomycin, another aminoglycoside, have indicated the potential for irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Animal studies conducted with plazomicin, the active ingredient in Plazomicin, did not show any drug-related visceral or skeletal malformations in pregnant rats and rabbits when administered during organogenesis at doses equivalent to or higher than the clinical dose. However, auditory function of offspring was not evaluated in these animal studies (refer to Data). Pregnant women should be informed of the potential risk to the fetus.

The background risk of major birth defects and miscarriage in the general population is unknown for the indicated patient population. In the general population of the United States, the estimated background risk of major birth defects is 2% to 4%, and the estimated background risk of miscarriage in clinically recognized pregnancies is 15% to 20%.

Data:

Animal Data:

In studies conducted with pregnant rats, subcutaneous administration of plazomicin at doses of 8, 25, and 50 mg/kg/day during organogenesis did not cause drug-related visceral or skeletal malformations or decrease fetal survival. Maternal toxicity, including reduced food consumption, body weight gain, and increased kidney weight, was observed at the mid and high doses. The high dose resulted in maternal exposure levels approximately 0.8-fold the human exposure (AUC) at the clinical dose of 15 mg/kg once daily.

In studies conducted with pregnant rabbits, subcutaneous administration of plazomicin at doses of 10, 30, and 50 mg/kg/day during organogenesis did not result in visceral or skeletal malformations or reduced fetal survival. Significant maternal toxicity, including renal injury and lethality, was observed at the high dose. Maternal exposure levels at the high dose were approximately 2.5-fold the human exposure (AUC) at the recommended clinical dose.

In a pre- and postnatal development study in rats, maternal animals were given subcutaneous plazomicin at doses of 3, 8, and 30 mg/kg/day from the beginning of organogenesis through lactation. No adverse effects on maternal function or the survival, development, behavior, or reproductive function of the offspring were observed at doses up to 30 mg/kg/day, which corresponds to approximately 0.32-fold the human exposure (AUC) at the clinical daily dose of 15 mg/kg.

Lactation:

There is limited information regarding the presence of Plazomicin in human milk and its potential effects on breastfed infants or milk production. Studies conducted in rats have shown the detection of plazomicin in rat milk, albeit at low concentrations (refer to Data). It is important to consider the developmental and health benefits of breastfeeding, alongside the clinical need for Plazomicin in the mother and any potential risks to the breastfed infant arising from Plazomicin or the underlying maternal condition.

Data:

In a study involving rats, small amounts of plazomicin were found in maternal milk, with mean concentrations representing 2% to 4% of maternal plasma concentrations. The systemic exposure (AUC) to plazomicin in nursing pups through lactational exposure was approximately 0.04% of the maternal systemic exposure.

Pediatric Use:

The safety and efficacy of Plazomicin in individuals below 18 years of age have not been established.

Geriatric Use:

Out of the 425 patients who participated in Trials 1 and 2, 40% (170/425) were aged 65 years and older, including 17.2% (73/425) who were 75 years and older. In Trial 1, among patients aged 65 years and older who received Plazomicin, the incidence rate of adverse reactions was 27% (37/137) compared to 18.9% (27/143) in patients of the same age group treated with meropenem. For patients younger than 65 years who received Plazomicin, the incidence rate of adverse reactions was 13.3% (22/166) compared to 24.1% (38/158) in the meropenem-treated patients in the same age group.

The rate of adverse reactions related to renal function in Plazomicin-treated patients aged 65 years and older was 6.6% (9/137) compared to 2.8% (4/143) in the meropenem-treated patients. For patients younger than 65 years who received Plazomicin, the incidence rate of adverse reactions associated with renal function was 1.2% (2/166), compared to 0% (0/158) in the meropenem-treated patients.

Plazomicin is primarily eliminated by the kidneys, and the risk of adverse reactions to Plazomicin may be higher in patients with impaired renal function. Considering that elderly patients are more likely to have reduced renal function, caution should be exercised when selecting the dosage, and renal function should be monitored. Dosage adjustment in elderly patients should take into account both renal function and plazomicin concentrations, as appropriate.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of overdosage of Plazomicin.

If an overdose of Plazomicin occurs, it is recommended to discontinue the medication and provide supportive care. It is important to maintain proper glomerular filtration and closely monitor renal function. Hemodialysis may be considered to assist in the removal of Plazomicin from the bloodstream, particularly if renal function is impaired or deteriorates. However, there is limited clinical information available regarding the use of hemodialysis specifically for the treatment of Plazomicin overdose.

Pharmacodynamics

Plazomicin exhibits its antibacterial activity in a manner dependent on the dosage, and it has been shown to have a post-antibiotic effect ranging from 0.2 to 2.6 hours at 2X MIC against Enterobacteriaceae in in vitro studies. In clinical trials involving hospitalized adult patients with complicated urinary tract infections (cUTI), including pyelonephritis, the administration of plazomicin resulted in the resolution or improvement of clinical symptoms associated with cUTI and demonstrated eradication of the causative microorganisms by day 5. It is important to note that plazomicin has the potential to cause nephrotoxicity, ototoxicity, and neuromuscular blocking effects. However, no clinically significant effects on QTc prolongation were observed in clinical trials.

Pharmacokinetics

Single- and Multiple-Dose Administration:

● Pharmacokinetic parameters of plazomicin were similar for single- and multiple-dose administration of Plazomicin in healthy subjects.

● No appreciable accumulation of plazomicin was observed following multiple intravenous infusions of 15 mg/kg administered every 24 hours in subjects with normal renal function.

Dose-Dependent Pharmacokinetics:

● The AUC, Cmax, and Cmin of plazomicin increased in proportion to the dose over the range of 4 to 15 mg/kg.

● Table 4 summarizes the pharmacokinetic parameters (geometric mean [±SD]) of plazomicin following administration of Plazomicin 15 mg/kg by 30-minute intravenous infusion in healthy subjects and patients with complicated urinary tract infections (cUTI).

Distribution:

● Volume of Distribution:

● The mean (±SD) volume of distribution of plazomicin was 17.9 (±4.8) L in healthy adults and 30.8 (±12.1) L in cUTI patients.

● Protein Binding:

● Approximately 20% of plazomicin binds to human plasma proteins.

● Protein binding was concentration-independent across the tested range of 5 to 100 mcg/mL.

Elimination:

● Total Body Clearance:

● The mean (±SD) total body clearance of plazomicin was 4.5 (±0.9) L/h in healthy adults and 5.1 (±2.01) L/h in cUTI patients.

● Half-Life:

● The mean (±SD) half-life of plazomicin was 3.5 hours (±0.5) in healthy adults with normal renal function.

Metabolism:

● Plazomicin does not undergo appreciable metabolic transformation.

Excretion:

● Primary Route of Excretion:

● Plazomicin is primarily excreted by the kidneys.

● Renal Clearance:

● The mean (±SD) renal clearance of plazomicin was 4.6 (±1.2) L/h, which is similar to total body clearance, indicating that plazomicin is eliminated by the kidneys.

● Urinary Excretion:

● After a single intravenous dose of 15 mg/kg radiolabeled plazomicin, 97.5% of the dose was recovered in the urine as unchanged plazomicin.

● Less than 0.2% of the administered dose was recovered in feces.

1. https://go.drugbank.com/drugs/DB12615

2. https://Plazomicin.com/

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5. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303Orig1s000lbl.pdf

6. https://www.webmd.com/drugs/2/drug-175512/plazomicin-intravenous/details