By
Liz Highleyman
Boosting
agents work by interfering with enzymes in the liver that process other drugs.
Ritonavir and the experimental booster GS-9350 both inhibit the action of the
CYP3A enzyme, slowing the processing -- and thereby raising blood levels -- of
other drugs metabolized by the same enzyme, including most protease
inhibitors (PI). Boosting allows PIs to be taken less often, with fewer pills,
and helps maintain an adequate level between doses. Unlike ritonavir, however,
GS-9350 does not have its own anti-HIV activity.
Gilead
researchers analyzed how well GS-9350 would boost the PI atazanavir. Since atazanavir
does not increase harmful blood lipids as much as other drugs in its class, it
is often prescribed for patients with elevated cardiovascular risk. Even the small
ritonavir dose (typically 100 or 200 mg) used for boosting can contribute to metabolic
problems, however, so a boosting agent without such side effects would be beneficial.
The
present study included 42 HIV negative volunteers. About two-thirds were men,
the average age was 28 years, two-thirds were white, and about one-quarter were
black.
Participants
first received 300 mg atazanavir plus either 100 mg or 150 mg GS-9350 or 100 mg
ritonavir, all taken with food for 10 days. They then underwent a 4-day "washout"
period to allow the drugs to leave their bodies, and crossed over to receive either
the other dose of GS-9350 or the other boosting agent. This was repeated a third
time, so all participants received all 3 boosting options in various orders.
Results
 | Atazanavir
levels were bioequivalent (functionally similar) in participants who took 100
mg ritonavir and 150 mg GS-9350, and but lower in those who received 100 mg GS-9350.
|
| The
atazanavir area under the curve (concentration across the dosing interval) was
similar with ritonavir and 150 mg GS-9350 (55,200 vs 55,900 ng*h/mL, respectively). |
| Maximum
atazanavir concentration (Cmax) was also similar in these 2 arms (5270 vs 4880
ng/mL, respectively). |
| Half-life
(how long the drug remains in the body) was comparable with ritonavir and the
higher GS-8350 dose (15.7 vs 16.7 hours, respectively). |
| 9
participants (21%) discontinued the study early, including 5 due to adverse events.
|
| 3
people taking GS-9350 stopped due to skin rash, which resolved after the drug
was discontinued. |
| Most
adverse events were mild to moderate. |
| No
serious grade 3-4 laboratory abnormalities or serious adverse events were reported,
including liver toxicity or clinically relevant heart rhythm (ECG) changes. |
| Elevated
bilirubin and jaundice -- known side effects of atazanavir -- were common and
comparable in the ritonavir and GS-9350 arms. |
These
findings led the investigators to conclude that 150 mg GS-9350 and 100 mg atazanavir
provided equivalent atazanavir exposures. GS-9350 was "safe and well tolerated,"
they added, and "may be a suitable alternative to ritonavir for boosting
of atazanavir."
A
Phase 2 study of treatment-naive HIV patients comparing 300 mg atazanavir plus
either 150 mg GS-9350 or 100 mg ritonavir plus tenofovir/emtricitabine (the drugs
in the Truvada coformulation)
is currently underway. GS-9350 is also being studied as part of a "quad"
pill containing tenofovir/emtricitabine and Gilead's investigational integrase
inhibitor elvitegravir.
Gilead Sciences, Foster City, CA.
9/29/09
Reference
S.
Ramanathan, D Warren, L Wei, and others. Pharmacokinetic boosting of atazanavir
with the pharmacoenhancer GS-9350 versus ritonavir. 49th Interscience Conference
on Antimicrobial Agents and Chemotherapy (ICAAC 2009). San Francisco. September
12-15, 2009. Abstract A1-1301.
