Pharmacokinetics, also known as PK, is the study of how medications behave in and move through the body. PK is used to figure out how much drug gets into your bloodstream and how long it stays there.

Scientists study PK to determine the best dose for an HIV drug. The dose must be high enough to keep HIV from reproducing, but not so high that it causes many side effects.

The following PK values are important:

• Maximum concentration (Cmax): highest drug level. When a drug is given, it reaches its peak level in the blood (Cmax) pretty quickly. The drug level then decreases as the drug is broken down and removed from the blood.
• Minimum concentration (Cmin): lowest drug level. The lowest drug level, right before the next dose, is the (Cmin), or “trough” level.
• Area Under the Curve (AUC): total drug exposure. The total exposure to the drug with each dose is called the AUC. (This refers to the graph of the drug level in the blood over time.)
• Half-life (t1/2): drug half-life. The t1/2 of the drug is the amount of time required for half of the drug to be removed from the bloodstream. For example, if the dose of a drug is 100 milligrams (mg), and the half-life is eight hours, 50 mg will be left after eight hours.

The PK values are used to figure out the correct dose – both the amount of drug and the schedule (once a day, twice a day, etc). In order for a drug to work, it must have a high enough minimum concentration (Cmin) and total exposure (AUC) to be effective against HIV.

It is also important to avoid toxic side effects. If the maximum concentration (Cmax) gets too high, the drug can cause many side effects. The goal of HIV therapy is to get the most benefit from the drug with the fewest side effects.

Last but not least, the half-life of the drug must be long enough to allow for a reasonable dose schedule. Many drugs are being developed with a long enough half-life so that they only need to be taken once a day.

Liver proteins called enzymes help with drug processing. Enzymes affect drugs by breaking them down. But enzymes are also affected by drugs.

This has proven to be very useful in HIV therapy. Here’s an example: Norvir (ritonavir) is a protease inhibitor (PI) that makes the enzymes work slower. This keeps other drugs in the body longer. So if Norvir is given with another PI, like Crixivan (indinavir), it “boosts” Crixivan. The minimum concentration (Cmin) and total exposure (AUC) of Crixivan are both increased.

As a result, Crixivan can be given twice a day with a little Norvir instead of three times a day by itself. The boosted regimen makes Crixivan easier to take. Several other PIs can be boosted with Norvir.

The NNRTIs (drugs like Viramune [nevirapine] and Sustiva [efavirenz]) have the opposite effect. They speed up enzymes and get other drugs out of the system faster. As a result, higher doses of other drugs may be required.

Doctors are aware of these interactions and will make sure you get the right doses. That’s why it is important to let your doctor know about all the medications and supplements you are taking (including herbs, prescriptions, over-the-counter, and street drugs).

There are some PK differences in men and women. At the same doses, some women have higher levels of certain drugs in their bloodstreams and experience more side effects (especially rashes) than men. Despite the differences, women seem to benefit as much from HIV therapy as men.

These PK sex (male vs female) differences may be related to hormone changes that occur when women get their periods. PK differences also may be linked to basic biology and physiology of cells (there are differences in the cells of men and women). They may also be linked to weight differences. Standard doses of drugs are usually based upon research done predominantly in men. This means a woman, who will generally weigh less than a man, may get a higher amount of the drug in her body than is needed to be effective. Although differences between men and women have been seen in studies, no changes to dosing have been recommended for women.

If you are experiencing side effects, ask your doctor for help. Do not change your dose or stop your drugs without speaking to your doctor.

Other factors can also affect PK, including:

• Genetic differences in drug processing
• Food
• Tobacco and alcohol use
• Medication interactions
• Race
• Hepatitis or other liver problems

Because of PK differences, new tests are being developed to help figure out if patients are receiving the right amount of drug.

Therapeutic Drug Monitoring (TDM): TDM is designed to measure your drug levels specifically. Basically it measures minimum concentration (Cmin) by drawing blood before morning meds. This will help your doctor to decide if your dose of medication should be changed.

Inhibitory Quotient (IQ): The IQ of a drug shows us how much drug should be necessary to inhibit the virus effectively. The IQ is different for each drug. This concept is still being proven.

The timing of medication doses has been carefully calculated to keep the drug in your bloodstream at levels that will control HIV. When you do not take a dose on time, the blood level of the drug will fall too low to be effective. 

When this happens your HIV may become resistant to the drug you are taking, causing it to stop working. Your viral load could go up, your CD4 cells could go down, and you might need to change drug treatments. The best way to avoid this is to take your pills the way they are prescribed. This maintains the blood level of the drugs necessary to fight the virus effectively.

1		Bean, P. (2000). HIV’s pharmokinetics, pharmacodynamics, pharmacogenetics, and pharmacodynamics. International Scientific Communications Publications: Retrieved July 2003 from http://www.iscpubs.com/articles/acl/c0011-12.bea.pdf.
2		Munk, B. (2001). The ups and downs of drug levels. Positively Aware: Retrieved July 2003 from http://www.thebody.com/tpan/mayjun_01/druglevels.html.
3		University of Liverpool. (2003). Antiretroviral pharmacokinetic fact sheet: Retrieved July 2003 from http://www.hiv-druginteractions.org/pharmacology/factsheets.asp.