Antiviral medications have a much harder time getting to work than you do. Sure, you have to deal with buses or subways, or traffic on your commute. But take a look at what your meds have to deal with! First they get swallowed and dumped into a pool of acid in your stomach. They get absorbed, mostly in the small intestine. From there, they go to the liver, which breaks down (metabolizes) and removes foreign substances from your blood. This process is called "first-pass metabolism." Some drugs make it through the liver untouched, but only a tiny fraction of other drugs get past this hurdle and into the bloodstream.
The amount of drug that makes it into your bloodstream, compared to the amount that you put into your mouth, is called "bioavailability." If a drug has low bioavailability, it means that a lot 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 dose you take has been increased to compensate for this.
Once drugs are in the bloodstream, they get carried throughout the body in about one minute. But they're still not ready to go to work. They have to move out of the bloodstream and into infected cells. Before this happens, they have to get past still more barriers.
The next hurdle is protein binding. Proteins in the blood (albumin and alpha-1 acid glycoprotein) latch onto most of the drug. This is a distribution system in the body. For example, adrenalin is produced in the kidneys. Without protein binding, it all might get absorbed in your gut. But blood proteins carry it around the body so that some of it gets to your heart and brain and it can have its full effect.
Protein binding is like a fleet of vans 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 vans is called the "free fraction," and that's the only amount that can leave the bloodstream and go to work. As the free fraction gets used up, the blood proteins gradually unload more of the drug. If a drug is "highly protein bound," it's possible that less than 1% of the amount that makes it into the bloodstream will be available for work.
Some areas of the body are "high security." For example, the "blood brain barrier," a tightly-woven network of blood vessels, protects our brain and spinal cord and keeps most antiviral drugs out. Another area of the body that drugs have a hard time penetrating is the genital area.
To get into infected cells, drugs have to get through the cell membrane, past the chemical "guards" that make sure only the right things get in. The nukes (nucleoside analog reverse transcriptase inhibitors) have an easy time getting in, because they look like the building materials that the cell needs in order to divide. Chemical "hands" pull them into the cell. Once inside the cells, the nukes have to go through three steps of chemical processing (phosphorylization) before they are ready to get to work.
Other antiviral drugs -- the NNRTIs and protease inhibitors -- have a harder time getting into cells. They don't look like anything the cell needs. They push their way in, but some of the drug gets pushed back out by a chemical "bouncer" called P-Glycoprotein.
Do We Have Enough?
With all of these barriers, as much as 99% of the medication we swallow might never get to fight the virus. So it's critical that we have enough drug in our bloodstream to start with. That's why drug companies study pharmacokinetics (far' muh ko kih NEH' tix), or PK.
PK measures the ups and downs of blood levels of drug in your body. For example, when you take a dose of a medication, the drug level goes up quickly. In a little while, it reaches its peak. This is called Cmax, the maximum concentration. As the drug gets removed from your body by the liver or kidneys, the blood level drops. Just before a new dose gets into your bloodstream, the blood level is the lowest. This is the "trough," or Cmin, the minimum concentration.
Another PK measurement is how long a drug stays in the bloodstream. This 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. This graph can be used to determine your total exposure to the drug. This is called the "area under the curve," or AUC, because it's calculated by measuring 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 a lot 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 have lower blood levels, while others have higher levels with the same dosing. PK results are based on the average for the people who were studied. Still, it's possible that you should use a lower dose if you don't weigh very much, or if you 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 levels if a drug doesn't seem to work the way it should.
How Is PK Used?
PK studies help drug companies choose a dose for a new drug that will be effective without causing too many side effects. But first, we need to set some limits on drug levels in the blood. We can draw two horizontal lines on our PK graph. The upper line represents the blood level where people start to develop serious side effects. The lower line represents the minimum drug levels that provide good control of the virus. This is usually the drug concentration that cuts down viral replication by 50%. This is called the "inhibitory concentration (50)" or IC50. We want to keep drug concentrations above the IC50, but below the level that will cause serious side effects. The zone between these two lines is called the "therapeutic window," the range of drug concentrations where it's doing more good than harm.
Each PK measurement puts some limits on the dosing:
The Cmax is related to short-term side effects like nausea or headache that hit after each dose. The Cmax has to stay low enough to keep these at a reasonable level.
The Cmin relates to control of the virus. If the Cmin drops too low, HIV can multiply and maybe develop resistance to the drug. The higher the Cmin, the better the viral control. Most manufacturers want to see the Cmin stay several times higher than the IC50.
The half-life of the drug helps decide how often you have to take it. Drugs with a long half-life stay in the blood longer, and you might only have to take them once or twice a day. If a drug has a short half-life, you might have to take it three or more times a day.
The AUC, which measures total exposure to the drug, is often related to control of the virus. The higher the AUC, the better the control. It can also be related to the amount of long-term side effects.
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.
They'll need to put more medication in each dose. Will that make the Cmax too high, and cause too much nausea and headache when each dose is taken?
Instead of about 8 hours between doses, it will now be 12 hours. If the drug has a long half-life, there won't be a huge difference in the minimum blood levels (Cmin). How does the new Cmin after 12 hours compare to the amount of drug needed to control the virus?
What's the AUC (area under the curve) using the new twice-daily dosing? If it's equal to or higher than the old AUC, then the new dosing is probably going to be just as powerful against the virus.
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.
The Best Curve Is a Straight Line
The ideal situation would be a constant level of drug in the body: enough to control the virus, but not enough to cause a lot of side effects. Instead of a graph showing peaks and troughs, we'd have a flat line. This will never happen if we swallow pills, because we get a large amount of drug with each dose. The only way to get constant drug levels is with an intravenous (IV) infusion, or with a pump like some diabetics use to take insulin. These methods of taking medication are more expensive and complicated than taking pills. Because they break the skin, there is a risk of infection.
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 drug is removed from the blood. The concentrations stay higher and the drug's half-life gets 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.
Pharmacokinetics gets pretty technical, but it's important for manufacturers to study drug levels to be sure that we can control the virus without too many side effects.
Bob Munk is the Coordinator of the New Mexico AIDS InfoNet at www.aidsinfonet.org, and is a frequent writer on AIDS treatment topics. He tested HIV positive in 1987.
AUC: Area under the curve, a measure of total exposure to a drug over a 24-hour period.
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%.
NNRTI: Non-nucleoside reverse transcriptase inhibitor, a type of antiviral drug. Examples are nevirapine (Viramune) and efavirenz (Sustiva).
Nuke: Nucleoside analog reverse transcriptase inhibitors, a type of antiviral drug. Examples are AZT (Retrovir) or d4T (Zerit).
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.)