GMHC Treatment Issues 1996 Sep 1; 10(9): 4
On September 27, the FDA's Antiviral Drugs Advisory Committee
will meet to consider licensing delavirdine (brand name:
Rescriptor). This Pharmacia & Upjohn product is the second
nonnucleoside reverse transcriptase inhibitor (NNRTI) to come
before the committee. (The first was Boehringer Ingelheim's
nevirapine -- see the June/July Treatment Issues, page 25).
Delavirdine is currently available to the public through an
expanded access program -- call 800/779-0070 for more
A major issue that remains unresolved with both delavirdine and
nevirapine is how these drugs affect the body's metabolism of
protease inhibitors. Like the protease inhibitor ritonavir,
both NNRTIs affect the CYP3A enzyme system in the liver that
breaks down many drugs. Nevirapine seems to increase
destruction of protease inhibitors whereas delavirdine (and
ritonavir) inhibits this loss. The result of these hepatic
changes on protease inhibitor blood levels or efficacy has been
little explored up to now.
Drug combinations that include both an NNRTI and a protease
inhibitor appeal to many people with HIV. First are those who
want to suppress HIV as much as possible early in disease
through a four drug combination that also includes two
nucleoside analogs. Then there are persons with advanced
infection who have had long histories with nucleoside analogs.
Their HIV may be largely resistant to these older agents.
As part of the run-up to the FDA meeting and to partially
satisfy intense public interest, Pharmacia & Upjohn has
released the preliminary results of its tests on combining
delavirdine with the three marketed protease inhibitors. These
initial data all come from tests with 13 or 14 HIV-negative
volunteers and are hardly enough to make final recommendations.
* For saquinavir (600 mg three times daily) plus delavirdine
(400 mg three times daily), there was a slight reduction in
delavirdine's mean trough plasma concentration (minimum level
between doses) while the mean tough levels of saquinavir
increased almost six-fold. Raising saquinavir levels to this
extent will make it a more potent drug, but the effect of
delavirdine varied greatly from person to person.
Furthermore, 13% of the volunteers experienced a rise in
blood levels of ALT, a liver enzyme whose blood levels go up
when the liver is inflamed. Doctors should monitor such
levels in patients taking delavirdine and saquinavir.
* Ritonavir was tested at 300 mg twice daily (half the standard
dose) along with delavirdine at 400 mg three times a day.
Ritonavir was unaffected, but a slight lowering of
delavirdine levels was seen. Full-dose ritonavir has yet to
be studied. In the meantime, Pharmacia & Upjohn is advising
"caution" when combining these two liver enzyme inhibitors.
* Indinavir so far has been tested as a single 400 mg or 600 mg
dose given to volunteers receiving 400 mg of delavirdine
three times a day. Delavirdine appeared to double the
effective dose of indinavir -- so that 400 mg of indinavir
resulted in the plasma levels usually found after 800 mg is
given. Based on this sketchy information, Pharmacia & Upjohn
is suggesting reducing the standard indinavir regimen of 800
mg three times daily to 400 or 600 mg three times daily when
delavirdine is coadministered. Beware that raising indinavir
blood levels heightens the risk of kidney stones.