Amadacycline

Uses

Amadacycline is a tetracycline antibiotic used to treat community acquired bacterial pneumonia.

Amadacycline is indicated for the treatment of community acquired bacterial pneumonia and acute bacterial skin and skin structure infections caused by omadacycline-susceptible organisms in adults.

Amadacycline is also used to associated treatment for these conditions: Acute Bacterial Skin and Skin Structure Infection (ABSSSI), Community Acquired Bacterial Pneumonia

How Amadacycline works

Amadacycline binds to the primary tetracycline binding site on the bacterial 30s ribosomal subunit with high specificity. There it acts to block protein synthesis, disrupting many facets of cellular function and resulting in either cell death or stasis.

Toxicity

No carcinogenicity studies have been conducted with Amadacycline, however, other tetracycline drugs have shown oncogenicity. Specifically, oxytetracycline increased incidence of adrenal and pituitary tumors and minocycline increased incidence of thyroid tumors.

Amadacycline has tested positive for clastogenicity and aneugenicity during in-vitro Chinese hamster ovary cell studies and for mutagenicity in mouse lymphoma cells. Both positive results occurred in the presence of metabolizing enzymes. Amadacycline has tested negative for chromosomal aberration of any kind during in-vitro Chinese hamster V79 cell testing. It has further tested negative during in-vivo micronucleus assays in ICR mice and HanRcc: WIST rats.

Amadacycline reduced sperm counts and sperm-motility in male rats at repeat dosages equivalent to 1.3 times the normal human exposure but produced no effect on fertility parameters. Inhibition of spermatogenesis was noted at repeat dosages equivalent to 6-8 times normal human exposure for a duration greater than 37 days but not at dosages under 2 times normal human exposure or durations of less than 4 weeks. Ovulation and embryonic survival was reduced in female rats at dosages approximating normal human exposure administered before mating through early pregnancy.

Thyroid hyperpigmentation, goitrogenicity, thyroid hyperplasia, and adrenal have been noted in multiple animal studies using other tetracycline drugs.

Food Interaction

• Avoid multivalent ions. Wait at least 4 hours after the omadacycline administration to take multivalent cations (eg. zinc, calcium, magnesium, and iron).
• Take on an empty stomach. Do not eat for 4 hours before and 2 hours after administering omadacycline. Drinking water after administration is acceptable.
• Take separate from antacids. Wait at least 4 hours after omadacycline administration to take antacids.

[Moderate] ADJUST DOSING INTERVAL: Administration with food, particularly dairy products, may reduce the absorption of omadacycline.

The calcium content of these foods may form nonabsorbable chelates with omadacycline.

MANAGEMENT: Amadacycline should be administered at least 2 hours before (4 hours for dairy products) or 4 hours after meals.

Amadacycline multivitamins interaction

[Moderate] GENERALLY AVOID: The bioavailability of oral tetracyclines and iron salts may be significantly decreased during concurrent administration.

Therapeutic failure may result.

The proposed mechanism is chelation of tetracyclines by the iron cation, forming an insoluble complex that is poorly absorbed from the gastrointestinal tract.

In ten healthy volunteers, simultaneous oral administration of ferrous sulfate 200 mg and single doses of various tetracyclines (200 mg to 500 mg) resulted in reductions in the serum levels of methacycline and doxycycline by 80% to 90%, oxytetracycline by 50% to 60%, and tetracycline by 40% to 50%.

In another study, 300 mg of ferrous sulfate reduced the absorption of tetracycline by 81% and that of minocycline by 77%.

Conversely, the absorption of iron has been shown to be decreased by up to 78% in healthy subjects and up to 65% in patients with iron depletion when ferrous sulfate 250 mg was administered with tetracycline 500 mg.

Available data suggest that administration of iron 3 hours before or 2 hours after a tetracycline largely prevents the interaction with most tetracyclines except doxycycline.

Due to extensive enterohepatic cycling, iron binding may occur with doxycycline even when it is given parenterally.

It has also been shown that when iron is administered up to 11 hours after doxycycline, serum concentrations of doxycycline may still be reduced by 20% to 45%.

Coadministration of a tetracycline with any iron-containing product should be avoided if possible.

Otherwise, patients should be advised to stagger the times of administration by at least three to four hours, although separating the doses may not prevent the interaction with doxycycline.

Amadacycline Disease Interaction

Major: colitis

Volume of Distribution

Amadacycline has a mean Vd of 256 L after a single dose and a Vss of 190 L.

Elimination Route

Amadacycline has an mean absolute oral bioavailability of 34.5% and a mean Tmax of2.5 h with oral dosing. With multiple dosing, Amadacycline displays an accumulation factor of 1.5. Official labeling states that food does not significantly impact rate or extent of absorption, however, conflicting data exists suggesting food may lower the bioavailability of omadacycline taken after eating. The exposure in alveolar cells and epithelial lining fluid is 25.8 and 1.5 fold higher than plasma exposure after IV administration, suggesting Amadacycline penetrates the lungs to a significant degree.

Half Life

Amadacycline has a mean half life of elimination of 16.2 h.

Clearance

Amadacycline has a mean systemic clearance of 11.24 L/h and a renal clearance of 2.4-3.3 L/h.

Elimination Route

After IV dosing 27% of Amadacycline was eliminated by the kidneys. In oral dosing 14.4% was found to be eliminated by the kidneys and 81.1% in the feces. Neither renal nor hepatic impairment appears to produce a clinically relevant effect elimination.

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