Case Studies and Project Ideas: Pharmacokinetics - Flucytosine

Simulation of Renal (Kidney) Failure

Goal:

To build and use a complex pharmacokinetic model to determine how kidney failure affects the pharmacokinetics of a drug.

Scenario:

A patient is admitted to the hospital with Candida Albicans, a yeast growth present in all of us and normally controlled by bacteria in the intestines. But when something destroys helpful bacteria, the yeast begins to invade and colonize the body tissues. These yeast colonies release powerful chemicals into the bloodstream, causing such varying symptoms as lethargy, chronic diarrhea, yeast vaginitis, bladder infections, muscle and joint pain, menstrual problems, constipation and severe depression. The medical term for this yeast overgrowth is candidiasis (can di di' a sis).

Candida overgrowth is not a new problem, but is usually thought of as a minor fungal infection of the mucous membranes, skin and nails. But the increased and sometimes excessive use of antibiotics, birth control pills and steroids will allow candidiasis to become a chronic, systemic infection that causes tissue damage throughout the body. Chemicals produced by the candida attack the immune system and if the immune system weakens, the candida will spread out into various body tissues and colonize. Candida is of particular importance in patients who are already immuno-suppressed due to the presence of the HIV/AIDS virus.

Candida can be controlled by a number of factors, including diet. However, in extreme cases, a series of anti-fungal agents, such as Flucytosine (5-FC) are often prescribed, usually in conjunction with one or more other medications. A profile of flucytosine is presented below:

Generic Name	Flucytosine (5-FC)
Brand Name	Ancobon
Indications	Systemic fungal infections. Typically used on combination with Amphotericin B.
Dose	50-200 mg/kg/day P.O. divided q 6 h, given for 2-6 weeks.
Route	PO
Levels and Metabolism	Maintain below the adult toxic range of 0.100-0.125 mg/ml.
Action	5-FC is believed to act by interfering with RNA, DNA, and protein synthesis. When used alone, resistance develops rapidly.
Toxicity	Enterocolitis, nausea, vomiting, diarrhea, rash, anemia, leukopenia, thrombocytopenia, elevated liver enzymes, increased BUN or creatinine, CNS derangements. Toxicity is frequent when given with Amphotericin B; Amphotericin may increase the toxicity of 5-FC by interfering with renal excretion. Dose-dependent leukopenia, with or without thrombocytopenia, can be fatal; it is more frequent when serum concentrations exceed 0.100 mg/ml.

Flucytosine is eliminated primarily through the kidneys, which use a structure known as a glomerulus to "filter" toxic chemicals from the blood and send them on to the bladder and the urine. Since kidney function is critical to prevent a toxic concentration of flucytosine, we wish to investigate what happens to the patient who experiences the failure of one kidney during the course of taking the drug. Your task is to first find a dosage and dosing interval that allows the patient to reach a therapeutic dose, then simulate the failure of one kidney and its effects on your therapeutic regime.

Building the Model:

In this model we are interested in five compartments:

Amount of drug in the intestine (in milligrams, or mg)
Amount of drug in the plasma
Amount of drug in the extracellular space (water outside of the cells of the plasma)
Amount of drug in the intracellular space
Amount of drugs being filtered through the kidneys

The model follows some fairly standard pharmacokinetic pathways. From the intestines, the drug is absorbed into the plasma. From the plasma, the drug can either be filtered into the kidneys, from where it is excreted. From the plasma the drug can also move through the capillaries of the blood system into the extracellular spaces. You may recall from biology that movement across a capillary is two-way, or bidirectional. In STELLA you can simulate this process by choosing the "Biflow" option when you define your flow. From the extracellular spaces, the drug can pass through the cell wall or cell membrane into the intracellular space. Movement across a cell membrane is also bidirectional.

We are fundamentally interested in measuring the concentration (in mg/mL) in the plasma, the intracellular space, and the extracellular space.

There is no drug present at the beginning of this four-day (192-hour) simulation. Use your reading of the drug specifications above to determine a therapeutic regime. Our patient is a 154-pound (70 kg) male in his late 30s. The therapeutic level is 0.05 mg/mL (concentration in the plasma, extracellular space, and intracellular space). In your initial runs, we wish to ensure that we do not exceed the toxic levels (some overshooting with the plasma concentration is acceptable, but is catastrophic if it happens in the extra- or intracellular spaces!). At the same time, we want the drug to do some good, so it has to reach a therapeutic effective level fairly quickly and stay there for the duration of the treatment (minimally four days).

The drug is absorbed into the plasma at a rate of 0.666 mg per hour. Filtration of the drug from the plasma is determined by:

Filtration = the concentration in the plasma (mg/mL) x the glomerular filtration rate (mL/hr)

The glomerular filtration rate is set at 130 mL/minute. We will use the STEP function in STELLA to simulate renal (kidney) failure at Day Two:

Renal Failure = STEP(-65,48), where the 65 is in units of mL/min, and 48 is in units of hours.

For now, do not include renal failure.

The drug is eliminated from the urine at a rate of 5.0 mL/hr.

The drug moves from the plasma to the extracellular spaces according to this algorithm:

Capillary movement = (concentration of the plasma (mg/mL) - concentration of the extracellular space) * 10000

The drug moves from the extracellular spaces to the intracellular spaces according to:

Movement across cell membrane = (concentration of extracellular space - concentration of intracellular space) * 10000

We also wish to know the half-life for this drug, based on this particular patient. Half-life is calculated:

Half-life = (0.693* Volume of distribution)/Clearance

Clearance for this drug is the same as the glomerular filtration rate.

The volumes for this model (in mL) are:

Volume of the plasma = 3000 mL

Volume of the extracellular space = 12,000 mL

Volume of the intracellular space = 24,500 mL

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