Ancobon Pharmacology, Pharmacokinetics, Studies, Metabolism - Flucytosine

Ancobon Pharmacology, Pharmacokinetics, Studies, Metabolism - Flucytosine

CLINICAL PHARMACOLOGY

Flucytosine is rapidly and virtually completely absorbed following oral administration. Bioavailability estimated by comparing the area under the curve of serum concentrations after oral and intravenous administration showed 78% to 89% absorption of the oral dose. Peak blood concentrations of 30 to 40 µg/mL were reached within 2 hours of administration of a 2-gm oral dose to normal subjects. The mean blood concentrations were approximately 70 to 80 µg/mL 1 to 2 hours after a dose in patients with normal renal function who received a 6-week regimen of flucytosine (150 mg/kg/day given in divided doses every 6 hours) in combination with amphotericin B. The half-life in the majority of normal subjects ranged between 2.4 and 4.8 hours. Flucytosine is excreted via the kidneys by means of glomerular filtration without significant tubular reabsorption. More than 90% of the total radioactivity after oral administration was recovered in the urine as intact drug. Flucytosine is deaminated (probably by gut bacteria) to 5-fluorouracil. The area under the curve (AUC) ratio of 5-fluorouracil to flucytosine is 4%. Approximately 1% of the dose is present in the urine as the a-fluoro-ß-ureido-propionic acid metabolite. A small portion of the dose is excreted in the feces.

The half-life of flucytosine is prolonged in patients with renal insufficiency; the average half-life in nephrectomized or anuric patients was 85 hours (range: 29.9 to 250 hours). A linear correlation was found between the elimination rate constant of flucytosine and creatinine clearance.

In vitro studies have shown that 2.9% to 4% of flucytosine is protein-bound over the range of therapeutic concentrations found in the blood. Flucytosine readily penetrates the blood-brain barrier, achieving clinically significant concentrations in cerebrospinal fluid. Studies in pregnant rats have shown that flucytosine injected intraperitoneally crosses the placental barrier (see PRECAUTIONS).

Pharmacokinetics in Pediatric Patients: Limited data are available regarding the pharmacokinetics of Ancobon administered to neonatal patients being treated for systemic candidiasis. After five days of continuous therapy, median peak levels in infants were 19.6 µg/mL, 27.7 µg/mL, and 83.9 µg/mL at doses of 25 mg/kg (N=3), 50 mg/kg (N=4), and 100 mg/kg (N=3), respectively. Mean time to peak serum levels was of 2.5 + 1.3 hours, similar to that observed in adult patients. A good deal of interindividual variability was noted, which did not correlate with gestational age. Some patients had serum levels > 100 µg/mL, suggesting a need for drug level monitoring during therapy. In another study, serum concentrations were determined during flucytosine therapy in two patients (total assays performed =10). Median serum flucytosine concentrations at steady state were calculated to be 57 + 10 µg/mL (doses of 50 to 125 mg/kg/day, normalized to 25 mg/kg per dose for comparison). In three infants receiving flucytosine 25 mg/kg/day (four divided doses), a median flucytosine half-life of 7.4 hours was observed, approximately double that seen in adult patients. The concentration of flucytosine in the cerebrospinal fluid of one infant was 43 µg/mL 3 hours after a 25 mg oral dose, and ranged from 20 to 67 mg/L in another neonate receiving oral doses of 120 to 150 mg/kg/day.

Microbiology: Flucytosine has in vitro and in vivo activity against Candida and Cryptococcus. Although the exact mode of action is unknown, it has been proposed that flucytosine acts directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism to 5-fluorouracil. Flucytosine enters the fungal cell via cytosine permease; thus, flucytosine is metabolized to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. Antifungal synergism between Ancobon and polyene antibiotics, particularly amphotericin B, has been reported.

Actions: Flucytosine has in vitro and in vivo activity against Candida and Cryptococcus. The exact mode of action against these fungi is not known. Ancobon is not metabolized significantly when given orally to man.

Susceptibility: Cryptococcus: Most strains initially isolated from clinical material have shown flucytosine minimal inhibitory concentrations (MIC’s) ranging from .46 to 7.8 µg/mL. Any isolate with an MIC greater than 12.5 µg/mL is considered resistant. In vitro resistance has developed in originally susceptible strains during therapy. It is recommended that clinical cultures for susceptibility testing be taken initially and at weekly intervals during therapy. The initial culture should be reserved as a reference in susceptibility testing of subsequent isolates.

Candida: As high as 40% to 50% of the pretreatment clinical isolates of Candida have been reported to be resistant to flucytosine. It is recommended that susceptibility studies be performed as early as possible and be repeated during therapy. An MIC value greater than 100 µg/mL is considered resistant.

Interference with in vitro activity of flucytosine occurs in complex or semisynthetic media. In order to rely upon the recommended in vitro interpretations of susceptibility, it is essential that the broth medium and the testing procedure used be that described by Shadomy.¹