The amount of drug that makes it into your bloodstream, compared to the amount that you put into your mouth, is called its "bioavailability." If a drug has low bioavailability, then much of the drug is destroyed by stomach acid, or is not absorbed in the small intestine, or is removed by first-pass metabolism in the liver. The amount of drug you take in a pill is calculated to correct for this so that the amount you need actually ends up in the blood.
Once drugs are past the liver, the bloodstream carries them throughout the rest of the body in about one minute. But they're still not ready to go to work. Now they have to move from the bloodstream and into the infected cells. But before this happens there are more barriers.
The next problem is called protein binding. Proteins in the blood (albumin and alpha-1 acid glycoprotein) stick to most of the drug in the bloodstream and hold it hostage. This is a normal way to distribute some messengers in the body. For example, adrenalin is produced in the kidneys. Without protein binding, it might get absorbed too soon. But blood proteins capture the adrenalin and carry it all around the body so that some gets to the heart and brain where it is needed.
Protein binding works like a fleet of trucks that load up most of the available drug supply and drive it to locations all over the body. The drug that's not loaded in the trucks is called the "free fraction." This is the only amount that is free to leave the bloodstream and go to work. As the free fraction is used up, the blood proteins gradually unload more of the drug. Some drugs are "highly protein bound" and can't get free. With certain drugs, less than 1% ever gets to leave the bloodstream and go to work in the cells.
Some areas of the body are "high security" zones. For example, the "blood brain barrier," a tightly woven network of blood vessels, protects our brain and spinal cord from toxins but also keeps most antiviral drugs out. Other areas the body protects from outsiders are the testicles and ovaries.
To get inside infected cells where they're needed, drugs have to pass through the cell's membrane. The membrane is protected by chemical "guards" that make sure only the right stuff gets in. For example, the nukes (nucleoside analog reverse transcriptase inhibitors, NRTIs) have an easy time getting past the membrane because they are so similar to natural building materials the cell uses when it divides. Chemical "hands" actually pull them into the cell. But once inside, the nukes still have to go through three more steps of chemical processing (called phosphorylization) before they are ready to work.
The other types of antiviral drugs -- the NNRTIs and PIs -- have a harder time getting inside cells because they don't resemble anything that the cell normally needs. Still, they can push their way inside -- even though a chemical "bouncer"called P-Glycoprotein might push some of the drug back out again.
PK measures the ups and downs of drug levels in your body. For example, when you take a dose of a medication, the drug level in the blood goes up quickly. In a little while, it reaches its peak. This is called Cmax -- the maximum concentration. As the drug is removed (metabolized) from your body by the liver or kidneys, blood levels of the drug drop. Just before the next dose enters your bloodstream, blood levels of the drug are at their lowest. This is called the "trough," or Cmin -- the minimum concentration.
Another PK value measures how long a drug stays in the bloodstream. It is calculated as the amount of time it takes for drug levels to fall by 50%. This is called the "half-life" of the drug.
If you draw a graph of drug levels in the blood, you will see that they rise quickly to the Cmax after a dose is taken, then fall off over time until the next dose.
The same graph can also be used to measure the total exposure to a drug. The "area under the curve," or AUC, is calculated by adding up the area under the curved line that charts the peak and trough levels of a drug.
Drug levels are different in different people. We all know some people who can eat constantly and stay thin, and others who seem to just look at food and gain weight. It's similar with drug levels. Some people "process" drugs quickly and so have lower blood levels -- while others have higher levels with the same dosing. Drug doses are based on PK averages for the people who were studied by the drug company. It's possible that a person should use a lower dose if they don't weigh very much, or if they have a slow metabolism. If you have a large body or a quick metabolism, you might need a higher dose. Your doctor might want to check your blood's drug level if a medicine doesn't seem to work the way it should.
Each PK measurement puts some limits on the dosing:
Let's say that a drug was approved based on three doses a day. Then the manufacturer wants to make it easier for patients to take, so they try to design a twice-daily dose. To do this, they will rely on PK data.
With a wide therapeutic window, it's easier to make some of these changes. There's more room to increase the dose without causing bad side effects, and more room (time) to let the blood level drop before it gets too low. With a narrow therapeutic window, there may be just one choice for dosing.
There is another way, however, to "smooth out" drug levels in the blood. Blood levels drop when the drug is metabolized by the liver and removed from the body. If we slow down this process, less of the drug is removed from the blood. The concentrations stay higher and the drug's half-life is extended.
The protease inhibitor ritonavir (Norvir) has this effect. For example, if the protease inhibitor indinavir (Crixivan) is used by itself, it has to be taken on an empty stomach, three times a day, once every eight hours. The "trough" levels are not much higher than the levels needed to stop the virus. But if indinavir is combined with a small amount of ritonavir, the trough levels of indinavir stay much higher, and you can take it just twice a day, with food. Ritonavir has a similar effect when it's combined with other protease inhibitors. These "ritonavir-boosted" regimens haven't been approved by the FDA yet, but are getting a lot of attention from researchers. Even though ritonavir is a protease inhibitor itself, its ability to slow metabolism of other drugs in the liver is a special use for the drug.
Pharmacokinetics can be very technical, but it's important to study drug levels to help let people control their virus without suffering too many side effects.
Bioavailability: A measure of how much drug makes it into the bloodstream, compared to how much we swallow.
Cmax: The maximum concentration of drug in the blood. It occurs shortly after taking a dose.
Cmin: The minimum concentration of drug in the blood. It occurs close to the time before the next dose is taken.
Half-life: A measure of how long a drug stays in the blood. The length of time it takes for the blood concentration to drop to 50% of Cmax.
IC50: Inhibitory concentration (50), the concentration of drug that cuts viral replication by 50%.
Pharmacokinetics: The study of how drug levels change over time in the body.
PI: Protease inhibitor, a type of antiviral drug. Examples: indinavir (Crixivan), nelfinavir (Viracept).
Protein binding: A process that inactivates some of the drug in the bloodstream and carries it throughout the body.
Therapeutic window: The difference or gap between the lowest drug concentration that is helpful (controls the virus), and the drug concentration that is harmful (causes too many side effects).
Back to the GMHC Treatment Issues July/August 2001 contents page.