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The ABCs of Pharmacokinetics
What's PK (Pharmacokinetics) Got to Do With It?

By Peter L. Anderson, Pharm.D.

Winter 2005

Pharmacokinetics (PK) is talked about a lot in the HIV community. PK is the study of what the human body does to drugs to get the drug out of the body. The main ways the human body handles drugs are listed below. These are all a part of PK.

Step 1. Drug absorption: This is how the drug enters the blood -- usually from tablets or capsules in the stomach and intestines. For some drugs, the amount of acid in the stomach, or the amount of food in the stomach, really changes the amount of drug that is absorbed. This is the reason that some drugs have "food requirements", or why some drugs have warnings not to take antacids along with the drug. (see Figure 1: Drug Metabolism Pathways):


Figure 1: Drug Metabolism Pathways


Step 2. Drug distribution: This is how the drug travels in the bloodstream and how it goes into and comes out of other areas of the body. Did you know that some areas of the body, like the brain and reproductive organs, are specially protected from chemicals (including drugs)? It is hard to measure drug levels in the brain and reproductive organs in people.

One way that drug distribution is studied in people is by finding out what percentage of the drug in the blood is stuck to proteins (called protein binding). This is important because only drug that is free of proteins can travel in and out of other areas of the body to be effective. Protein binding is often studied when a drug is being developed by a drug company. However, protein binding is not routinely studied after that because knowing the total blood concentration (both protein-bound plus protein-free) is generally good enough.

Step 3. Drug metabolism: This is how the body chemically changes a drug -- usually in the intestines and liver. Metabolism involves breaking a drug down or adding a chemical that makes it easier to pass it into urine or stool. A lot of drug-drug interactions happen because one drug interferes with the metabolism of another drug (called inhibition). Inhibition causes higher drug levels. On the other hand, a drug can also speed up the metabolism of another drug (called induction). Induction causes lower drug levels.

The CYP-450 (pronounced "sip") enzyme system is a well-known group of human enzymes that metabolize drugs and chemicals in the body. CYP-450 enzymes are mostly in the intestines and liver.

The CYP-450 enzymes are broken into three families (CYP1, CYP2 and CYP3) (see Figure 2: Antiretrovirals and CYP-450 Isoenzymes). When doctors and pharmacists talk about the CYP-450 system, they often just refer to the system as CYP and drop the 450 part. Within the CYP-450 system, though, there are different enzyme families. To distinguish one family from another, a letter and number are added to CYP (again, dropping the 450 numbering). Some examples of this are CYP1A2, CYP2D6, CYP3A4, etc. (Note how the 450 is dropped, but the CYP remains.)

Figure 2: Antiretrovirals and CYP450 Isoenzymes
Pyramid depicts the various CYP 450 enzymes in the body and the drug interactions with antiretrovirals. CYP3A4, shown at the top of the pyramid and largest single part of the pyramid, is very important. Arrows point to the various antiretrovirals and the general affect(s) that medicine has on that enzyme. Note that drugs can be listed as both an inducer and inhibitor and with multiple enzymes.
Each CYP has a different ability to metabolize a given chemical or drug. For example, CYP3A4 is probably the most important drug metabolizing enzyme because it metabolizes the most drugs, including protease inhibitors.

Norvir strongly inhibits CYP3A4 and causes most of the other protease inhibitors to build up in the blood. This is called Norvir boosting. For the protease inhibitors that are boosted by Norvir, the higher blood levels may help the "boosted" drug work better. But, for other drugs that are metabolized by CYP3A4, like cholesterol drugs or erectile dysfunction drugs, Norvir and protease inhibitors may cause undesirable increases in blood concentrations (see Protease Inhibitor article).

Step 4. Drug elimination: This is how the body gets the drug out -- usually by passing the drug into the urine (via the kidneys) or stool (via the liver). Sometimes people have some kidney or liver illness. In these people, the blood level of some drugs may build to very high levels if the drug dose is not reduced (see Figure 1: Drug Metabolism Pathways).


PK Definitions

There are certain terms and tests that researchers or doctors use when they study PK. The following is a summary of these PK measurements and what they mean. Please refer to Figures 3 and 4 for a picture of what all these PK measurements represent.

Figure 3: Blood Levels of a Drug Over Time
Above are blood levels (Y-axis) of a drug over time (X-axis) after a patient takes a single dose. In this representation, the patient took the dose at time 0 and would be due for another dose at time 12 (hours). Since the time 0 level is about equal to the time 12 level, the patient is at steady state. For AUC measurements, blood levels are usually collected every hour or so. Figure No. 4 below is another way of looking at these same concepts.
Figure 4: Concentration-Time Curve at Steady-State

AUC (area-under-the-curve): This is the overall amount of drug in the bloodstream after a dose. AUC studies are often used when researchers are looking for drug-drug or drug-food interactions. The way to get an AUC involves collecting many blood samples (usually every one or two hours) right after a person takes a dose up until the next dose is due. In each blood sample, the concentration of the drug is measured with a machine (discussed later). Then all the drug concentrations are put onto a graph based on the time after the dose that they were collected. A curve is made by connecting the points on the graph. The AUC for that drug is then calculated as the area under this drug concentration curve. An AUC study contains a lot of information about PK. It is probably the best way to understand how people handle a drug (PK).

Cmax (maximum concentration): This is the highest concentration of drug in the blood that is measured after a dose. Cmax usually happens within a few hours after the dose is taken. The time that Cmax happens is referred to as Tmax. For some antiretroviral drugs, a high Cmax is thought to increase the risk of side effects from the drug.

Cmin or trough (pronounced "troff") (minimum concentration): This is the lowest concentration of the drug in the blood that is measured after a dose. It happens right before a patient takes the next usual dose. It is not known for certain, but many people in the HIV community believe that keeping the trough concentration (Cmin) above a certain level is especially important for anti-HIV activity.

Half-life (t ½): This is the amount of time it takes for the drug concentration in the blood to decline by half. The half-life is among the most important PK measurements for how often a drug has to be dosed (once-a-day or twice-a-day, etc).

Steady-state: This means that a person has been on a drug for enough time (usually one to two weeks) so that the drug concentration is not building up in the bloodstream anymore. The time it takes to get to steady-state depends on the half-life of the drug. A drug gets to steady state in about five half-lives.

As an illustration, before a patient reaches steady-state, each additional dose may be building the drug up in the body so each dose would be giving a higher Cmax, Cmin, and AUC. But, at steady-state, every dose would give the same Cmax, Cmin, and AUC in the patient because it is not building up any more.

Adherence: Remarkably, antiretroviral regimens lose effectiveness even with a small drop from perfect (or near-perfect) adherence. For example, going from 95?100% adherence down to 90?95% adherence with protease inhibitors resulted in a drop in effectiveness (viral load below 400) from 81% to 64%. It seems that the usual drug levels are not much higher than what?s needed for sustained efficacy. Additionally, the half-lives of the agents must have been relatively fast, such that the drug exposure fell below a level associated with a high probability of efficacy after the missed dose. Obviously, taking as close to 100% of antiretroviral doses is critically important.

Once-a-day dosing: Once daily combination antiretroviral therapies is a newer concept that is targeted to improve adherence. Several once-daily regimens are now available where all drugs have similar dietary requirements so that the whole regimen can be taken at the same time (see Figure 7: Options for Once-daily Dosing). It should be noted that only approved once-daily combinations should be used at this time (such as Truvada plus Sustiva as initial therapy). Some other antiretrovirals are currently approved for twice-a-day dosing, but they are being studied as once-a-day drugs. These "investigational" regimens should only be used in very controlled settings (like in a study). This is because it is not yet known if "investigational" drugs provide the right amount of drug exposure for effective and safe once-daily dosing (especially if a dose is missed). Which is better -- once-a-day or twice-a-day dosing? The conservative answer is: both. In studies done to date comparing once- to twice-a-day dosing, they come out equal at the end.

Figure 7: Options for Once-Daily Therapy

Pharmacodynamics (PD): PD is just a fancy term for drug efficacy and toxicity. PD refers to what the drugs do to the human body. For example, HIV drugs cause HIV viral load to decline and CD4 cells to increase. Also, drugs sometimes cause certain side effects and toxicity in the human body.


What's PK Got to Do With It?

PK is studied a lot in HIV and it is important for many reasons.

First of all, the PK of many HIV drugs is really changed by certain things. For example, the blood levels of HIV drugs can be increased or lowered by not following the food requirements with dosing, taking antacids with the drugs, or taking certain other drugs or herbals that cause big inhibition or induction interactions (see metabolism above). It is important to find the dose requirements out so that patients know how best to take the drugs.

Secondly, every person who takes HIV drugs is a bit different in the way their body handles these drugs (absorption, distribution, metabolism, and/or elimination). This means that a patient can have high or low blood levels after taking the same dose just because of the way they handle the drug.

Finally, all of this matters because the levels of drugs in your body affect how well the drug works against the virus or whether the drug might cause side effects. In the case of high levels there could be more side effects. Poor efficacy against HIV could result from low levels. In some special cases, your doctor may think that it might be a good idea to measure the blood levels of your drugs. Based on the result, your doctor may adjust your doses and then re-check your blood levels of drug to try and get them right where they want them. This is called "therapeutic drug monitoring" (TDM).


Measuring Drug Levels

Determining your drug levels from blood samples is usually only done in specialty labs. These labs use machine tests called "high performance liquid chromatography (HPLC or LC)" and sometimes "mass spectrometry (MS)". This is generally how it works: Your blood is collected in a tube. The tube is spun very fast in a centrifuge to get the red blood cells to sink to the bottom of the tube leaving the plasma on the top. This is done because the drug level is actually measured in the plasma.

Once at the lab, the drug needs to be purified from the plasma because the plasma is also full of a lot of other things besides the drug (sort of like filtering the drug out). This "filtering" step usually leaves a liquid with the purified drug in it. This purified drug portion is then put into an HPLC machine that filters the drug to make it even more purified and then pumps the drug to a detector.

There are a lot of different kinds of detectors. The common ones for HIV drugs are a mass spectrometer (MS) and an ultraviolet light absorbance detector (UV). A MS detects drugs according to how heavy it is (and also the positive and negative charge of the drug). The detector gives a signal based on how much drug is there. The signal is compared with signals that the detector gives for known amounts of drug that are also put onto the machine (called a standard curve). This gives the drug level in the patient.


Important Things About PK and TDM

One important point is that TDM is not really useful for nukes in most cases. This is because nukes have three phosphate groups attached while inside cells in order to become active against HIV (called triphosphates). Therefore, the best way to do TDM for nukes would be to measure the nuke-triphosphates that are in cells, not the plasma level of the nuke. But, this is very hard to do, so TDM for nukes is not usually done.

Since nuke-triphosphates inside cells are really important for anti-HIV activity, it is important for researchers to measure the half-life of the triphosphate in patients to understand whether the nuke can be given once a day, twice a day, and so on. For many nukes, the half-life of the triphosphate in cells is quite a bit longer than the half-life in plasma, so the nuke can be given once or twice a day (see Figure 5: Plasma and Intracellular Half-lives of Select NRTIs).

Figure 5: Plasma and Intracellular Half-Lives of Select NRTIs
This figure depicts the half-lives of select nukes. Note how the half-life in the plasma is always much shorter than the half-life within the cell. Two examples of this are shown with Viread and Emtriva.
As an example, Ziagen (abacavir) has a fast half-life (about 1.5 hours) in plasma, but the half-life of the triphosphate in cells is about 20 hours. So, abacavir can be given once a day.

On the other hand, PIs and NNRTIs are not chemically changed in cells to become active, so the plasma levels can be used for TDM. But, TDM is not routinely used in the U.S. for several reasons. First, TDM has not really been studied much in patients, so doctors are not yet sure about TDM in all their patients.

Secondly, it is not yet clear exactly how to use the information TDM provides. There are some questions that are still unanswered regarding TDM, including:

  1. What are the target levels for efficacy in patients with resistant viruses? Right now, levels that are recommended in treatment guidelines are only for viruses that are not resistant. If a person has a resistant virus, precisely how much of the drug they should have in their body is unknown.
  2. How is it best to adjust doses to meet targets -- for example, should Norvir boosting be the main way to increase levels for PIs?
  3. Are Cmax levels useful for reducing toxicity?
  4. Is an expert needed to do TDM?
  5. And, should laboratories be required to pass the same quality assurance test to get official approval to do the levels?

Figure 6: Suggested Minimum Target Trough Concentrations for Persons With Wild-Type HIV-1
This table provides suggested trough (Cmin) concentrations for people taking these drugs who do not have a resistant virus.
Although TDM may not be used routinely in all patients, there are some situations where TDM may be useful. These include: childhood, obesity, very small body size, elderly, pregnancy, liver or kidney diseases, and drug-drug interactions. Also, TDM may be used in patients with an unexpected adverse effect or poor efficacy. For these occasions, as mentioned above, there are suggested target levels for PIs and NNRTIs in situations where there is no drug resistance (see Figure 6: Suggested Minimum Target Trough Concentrations for Persons with Wild-type HIV-1).

Finally, if TDM is to be undertaken, there are some very important things to do. First, if the level is for efficacy, it is very important to get the level as close to the trough as possible. This is the best way to interpret the level.

If the level is for toxicity, and a Cmax is desired, it would be best to watch the dose being taken and to obtain the level thereafter. In general, it is very important to realize that the TDM test completely depends on accurately recording when the patient last took their dose and accurately recording when the blood was collected. Other drugs that might have been taken with the dose should also be recorded. Since the current state of TDM for HIV is in the development phase, it would be best to obtain expert advice if undertaking TDM.

Peter L. Anderson, Pharm.D., is an Assistant Professor of Pharmacy, Department of Clinical Pharmacy, University of Colorado Health Sciences Center, Denver. His main experience is pharmacokinetics and pharmacodynamics of anti-HIV drugs and he has been involved in the field for 6 years.

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