Tedizolid Phosphate

Absorption

Tedizolid reaches peak plasma concentrations within three hours for oral administration and within one hour following intravenous administration; the absolute oral bioavailability is approximately 91%. Food has no effect on absorption. When given once daily, either orally or intravenously, tedizolid reaches steady-state concentrations in approximately three days.
The Cmax for tedizolid after a single dose/at steady-state is 2.0 ± 0.7/2.2 ± 0.6 mcg/mL for oral administration, and 2.3 ± 0.6/3.0 ± 0.7 mcg/mL for intravenous administration, respectively. Similarly, the Tmax has a median (range) of 2.5 (1.0 - 8.0)/3.5 (1.0 - 6.0) hrs for the oral route and 1.1 (0.9 - 1.5)/1.2 (0.9 - 1.5) hrs when given intravenous. The AUC is 23.8 ± 6.8/25.6 ± 8.4 mcg*hr/mL for oral and 26.6 ± 5.2/29.2 ± 6.2 mcg*hr/mL for intravenous.

Toxicity

Toxicity information regarding tedizolid is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as nausea, headache, dizziness, diarrhea, and vomiting. Symptomatic and supportive measures are recommended.

Description

Tedizolid phosphate was approved by the US FDA in June 2014 for treatment of acute bacterial skin and skin structure infections caused by susceptible gram-positive pathogens, including MRSA. Tedizolid phosphate was discovered by Dong-A Pharmaceuticals in South Korea and developed in the USA by Cubist Pharmaceuticals (acquired from Trius Therapeutics in 2013, became a wholly owned subsidiary of Merck in 2015). The worldwide commercialization rights for tedizolid phosphate are divided between Cubist in the USA, Canada, and EU, and Bayer in Asia–Pacific, Latin America, and Africa. This second-generation oxazolidinone prodrug is rapidly converted to the active form tedizolid in the presence of endogenous phosphatases. It inhibits bacterial protein synthesis by binding to the 23S ribosomal RNA of the 50S subunit of the ribosome, preventing formation of the 70S ribosomal initiation complex, and is 4-fold to 16-fold more potent against staphylococci and enterococci compared to linezolid. 251 With high oral bioavailability (approximately 90%) and long half-life (approximately 12 hours), tedizolid phosphate is the first oxazolidinone antibiotic which can be dosed once daily either orally or intravenously.

The Uses of Tedizolid Phosphate

Tedizolid, known as TR-700, is an oral and i.v administered intracellular antibacterial drug.

Background

Drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and penicillin-resistant Streptococcus penumoniae, represent a massive public health threat. Tedizolid is a member of the oxazolidinone class of antibiotics, which includes the previously approved linezolid and is generally effective against multidrug-resistant Gram-positive bacteria. Tedizolid is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and is generally more effective and more tolerable than linezolid.
Tedizolid was approved by the FDA on June 20, 2014, for sale by Cubist Pharmaceuticals as tedizolid phosphate (SIVEXTRO?). This product is currently available as both an oral tablet and as a powder for intravenous injection.

Indications

Tedizolid is indicated for the treatment of acute bacterial infections of the skin and skin structure (ABSSSI). To prevent drug resistance, tedizolid should only be used for infections that are caused by susceptible bacteria.

Definition

ChEBI: A phosphate monoester resulting from the formal condensation of equimolar amounts of phosphoric acid with the hydroxy group of tedizolid . It is a prodrug of tedizolid, used for the treatment of acute bacterial skin infections caused by certain susceptibl bacteria, including Staphylococcus aureus (including methicillin-resistant strains (MRSA) and methicillin-susceptible strains), various Streptococcus species, and Enterococcus faecalis.

Pharmacokinetics

Tedizolid is an oxazolidinone antibiotic that works by inhibiting protein synthesis by bacterial ribosomes. However, oxazolidinone antibiotics can also bind to human mitochondrial, but not cytoplasmic, ribosomes. Mitochondrial protein synthesis inhibition is associated with adverse patient effects such as neurological, hematological, and gastrointestinal toxicity, although tedizolid is tolerated better than the related linezolid. Alternative therapies should be considered when treating neutropenic patients with ABSSSI. Clostridium difficile-associated diarrhea has been reported in patients treated with tedizolid.

Clinical Use

Reversible non-selective MAO inhibitor:
Antibacterial agent

Synthesis

Commercial 5-bromo-2-cyanopyridine (260) was treated with sodium azide and ammonium chloride in DMF to produce tetrazole 261, which was isolated by precipitation of the tetrazole ammonium salt. Subsequent methylation with methyl iodide in THF/DMF (3:1) afforded a 3.85:1 mixture of 262 and the corresponding N1-regioisomer. Acidification with 6 M HCl followed by treatment with 50% aqueous NaOH (to pH 10.6) enabled isolation of 262 in 96% isomeric purity; crude 262 was further purified by recrystallization from isopropyl acetate and obtained in 33% yield from 261. A Suzuki reaction of 262 with boronic acid 263 (which was prepared from commercial 4-bromo-3-fluoroaniline (267) as described in Scheme, via carboxybenzyl (Cbz) protection and lithiation/borylation) followed by recrystallization from ethyl acetate produced triaryl system 264. Deprotonation of the carbamate within 264 using lithium hexamethyldisilazide (LiHMDS) followed by reaction with R-(-)-glycidyl butyrate (265) in the presence of 1,3-dimethyl tetrahydropyrimidin-2 (1H)-one (DMPU) generated tedizolide 266 in 85% yield. Reaction with POCl3 in THF at 1¨C2 ?? followed by subjection to sodium hydroxide and subsequent acidification furnished tedizolid phosphate (XXXIII) in 76% yield across the three steps.

Drug interactions

Potentially hazardous interactions with other drugs
Alcohol: some alcoholic and de-alcoholised drinks contain tyramine which can cause hypertensive crisis.
Alpha-blockers: avoid concomitant use with indoramin; enhanced hypotensive effect.
Analgesics: CNS excitation or depression with pethidine, other opioids and nefopam - avoid; increased risk of serotonergic effects and convulsions with tramadol - avoid.
Antidepressants: enhancement of CNS effects and toxicity; avoid MAOIs, SSRIs and vortioxetine for 2 weeks after use; care with all antidepressants.
Antiepileptics: antagonism of anticonvulsant effect; avoid carbamazepine with or within 2 weeks of MAOIs.
Antimalarials: avoid concomitant use with artemether/lumefantrine and piperaquine with artenimol.
Antipsychotics: effects enhanced by clozapine.
Atomoxetine: possible increased risk of convulsions - avoid concomitant use and for 2 weeks after use.
Bupropion: avoid with or for 2 weeks after MAOIs.
Dapoxetine: increased risk of serotonergic effects, avoid with or for 2 weeks after MAOIs.
Dexamfetamine and lisdexamfetamine: risk of hypertensive crisis, avoid with or for 2 weeks after MAOIs.
Dopaminergics: avoid concomitant use with entacapone and tolcapone; hypertensive crisis with levodopa and rasagiline - avoid for at least 2 weeks after stopping MAOI; hypotension with selegiline.
5HT1 agonist: risk of CNS toxicity with sumatriptan, rizatriptan and zolmitriptan - avoid sumatriptan and rizatriptan for 2 weeks after MAOI.
Metaraminol: risk of hypertensive crisis, avoid with or for 2 weeks after MAOIs.
Methyldopa: avoid concomitant use.
Opicapone: avoid concomitant use.
Sympathomimetics: hypertensive crisis with sympathomimetics - avoid.
Tetrabenazine: risk of CNS excitation and hypertension - avoid.

Metabolism

Tedizolid is administered as a phosphate prodrug that is converted to tedizolid (the circulating active moiety). Prior to excretion, the majority of tedizolid is converted to an inactive sulphate conjugate in the liver, though this is unlikely to involve the action of cytochrome P450-family enzymes.

Metabolism

Tedizolid phosphate is converted by endogenous plasma and tissue phosphatases to the microbiologically active moiety, tedizolid.
Tedizolid is eliminated in excreta, primarily as a noncirculating sulfate conjugate. Following single oral administration of [14C]-labelled tedizolid under fasted conditions, the majority of elimination occurred via the liver with 81.5% of the radioactive dose recovered in faeces and 18% in urine.