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The primary drug used,
quite successfully, in improving the pharmacokinetics of ARV
is ritonavir (Norvir). Agents recently brought and on the
way to market would never have made it out of Phase I/II trials
were ritonavir not combined with them (lopinavir/ritonavir—Kaletra
and tipranavir/ritonavir—
Boehringer-Ingelheim’s experimental protease inhibitor,
respectively). Ritonavir in combination with other approved
agents, such as indinavir (Crixivan), amprenavir (Agenerase),
hard-gelatin saquinavir (Invirase) and soon atazanavir (Reyataz)
has allowed clinicians to use these agents at altered doses
and frequencies that would not be available otherwise. Perhaps
the most important result of combining these agents with ritonavir
is not that the results are that much better, but the ability
of the patient to incorporate the dosing into their lives
was significantly enhanced.
Taking ritonavir as part
of ARV can have its drawbacks, however. Low-dose ritonavir
can still impact triglycerides, and to a lesser degree cholesterol,
but still carries serious drug interaction potential. This
is, after all, why ritonavir is being used in the first place—its
ability to interfere with the body’s breakdown of another
medicine is such that a lower dose of the other agent (and
usually less often dosed) can be used. This may help to improve
the tolerability of the other agent, but close watch needs
to be maintained on any and all other medicines (including
non-ARV) a person may be taking. (Ask your pharmacist!)
Nelfinavir (Viracept) does
not have much in the way of dosing changes when given with
ritonavir. The way it is broken down and eliminated by the
body is not impacted to any appreciable degree by ritonavir.
It has been shown that a significant change can be seen in
the amount of nelfinavir in the body from one dosing time
to the next, but it was not due to a missed dose of another
medication. Instead, the amount of nelfinavir that gets into
the body has been shown to be affected by the amount and type
of food ingested with it.
The original nelfinavir studies
revealed that if a single 250 mg tablet was taken with food
versus an empty stomach, the amount of drug in the blood (over
the dosing interval—or AUC, for “area under the
curve”) was one to two times as much. This is very important
because a certain amount of drug has to be maintained in the
body in order for a drug to work against the virus.
A recently reported study
done in Europe (ATHENA) took patients on nelfinavir and sampled
the amount of drug in their blood. They then took the patients
with lower levels than what was considered acceptable and
gave them more detailed instructions on eating around the
time of their nelfinavir dose. Over 1/3 of the patients who
then ate more (increased calories and fat) around the time
of their nelfinavir dose had their levels come up into the
acceptable range without having to alter their dose—or
take another medicine. This also increased the percent of
persons with undetectable viral loads from 58.8% to 80.5%
after one year.
This data was looked at in
a more structured fashion by the manufacturer. Diets of 1,000
kcal (50% fat), 500 kcal (20% fat) and 125 kcal (20% fat)
were compared to each other and then to fasting in the same
subjects. It was presented that the amount of drug in the
body when eating instead of fasting was 3–5 times as
much compared to fasting. What was even more intriguing was
that the amount of drug in the blood just before the next
dose was more consistent and higher when the subjects ate
instead of fasting.
On the heels of this information
is the newest dosage unit of nelfinavir, the 625 mg tablet.
Recently approved by the FDA, this new tablet allows patients
to take two pills twice a day instead of the 10 daily needed
with the 250 mg tablet strength. The tablets are fairly close
in makeup with some minor differences seen in the amount of
blue dye and silicon (more and less in the 625 mg tablet,
respectively). However, just like with the 250 mg tablet,
eating makes a difference in how much gets into the body.
The amount of drug that got into the body was twice as much
when taken with food compared to fasting.
As we continue to move further
away from the “hit hard, hit early” and closer to
the “wait and see” approach to treating HIV infection,
what has remained consistent is the need to make every regimen
count for as long as possible. Providing information on the
importance of diet to each ARV should be a standard part of
every counseling session with patients at every visit.
Patrick G. Clay, PharmD
is an Assistant Professor of Pharmacy Practice at the University
of Missouri-Kansas City School of Pharmacy. He is also the
HIV Clinical Specialist at the KC Free Health Clinic, 3515
Broadway, Kansas City, MO 64111. Dr. Clay can be reached by
phone: (816) 777-2721; fax: (816) 753-0804; or e-mail: claypg@umkc.edu.
Editor’s note: Please see “Viracept
and food” in News Briefs.)
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