|
by Bob Munk
Antiviral medications have
a much harder time getting to work than you do. Sure, you
have to deal with busses 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 PIs—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.
Glossary
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.)
|
