DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1656 tipranavir/ritonavir or a comparator PI regimen, 34% had at least
a one log sustained drop in plasma HIV RNA by week 48 compared
to 15% of controls. However, 5.4% of tipranavir recipients
discontinued treatment because of adverse events, compared to
1.6% of controls (Orman and Perry, 2008). Combining tipranavir
with at least one other active antiretroviral drug, usually enfuvirtide,
greatly improved virologic responses in these studies.
Tipranavir/ritonavir is approved for use in adults and pediatric
patients >2 years of age, with pediatric dosing based on weight or
body surface area.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
ENTRY INHIBITORS
There are two drugs available in this class, enfuvirtide
and maraviroc, that have different mechanisms of
action (Figure 59–1). Enfuvirtide inhibits fusion of the
viral and cell membranes mediated by gp41 and CD4
interactions. Maraviroc is a chemokine receptor antagonist
and binds to the host cell CCR5 receptor to block
binding of viral gp120. As such, maraviroc is the only
approved antiretroviral drug that targets a host protein.
One other CCR5 receptor antagonist, vicriviroc, is in
advanced clinical development.
CXCR4, the co-receptor for T-lymphocyte tropic HIV, would
seem to be an equally good target for antiretroviral drug development.
However, two investigational CXCR4 antagonists produced
no substantial drop in plasma HIV RNA in most treated patients,
even though they efficiently eliminated CXCR4-tropic virus from
the circulation (Stone et al., 2007), suggesting that these drugs cause
rapid selection for HIV that is CCR5-tropic. Although these compounds
are no longer in development for HIV infection, they do
cause an increase in circulating leukocytes, presumably as a direct
consequence of CXCR4 blockade. One of these compounds, plerixafor,
is now approved as an adjunct to stem cell mobilization after
cancer chemotherapy (Chapter 37).
Maraviroc
Chemistry and Mechanisms of Action and Resistance.
Maraviroc blocks the binding of the HIV outer envelope
protein gp120 to the CCR5 chemokine receptor (Figure
59–7). Maraviroc is active only against CCR5-tropic
strains of HIV and has no activity against viruses that
are CXCR4-tropic or dual-tropic. The reported in vitro
IC 50
for CCR5-tropic HIV-1 ranges from 0.1 to 4.5 nM
depending on the virus strain and testing method
employed (MacArthur and Novak, 2008). Maraviroc
retains activity against viruses that have become resistant
to antiretroviral agents of other classes because of
its unique mechanism of action.
HIV can develop resistance to this drug through two distinct
pathways. A patient starting maraviroc therapy with HIV that is predominantly
CCR5-tropic may experience a shift in tropism to
CXCR4- or dual/mixed-tropism predominance. This is especially
likely in patients harboring low-level but undetected CXCR4- or
dual/mixed-tropic virus prior to initiation of maraviroc. Alternatively,
HIV can retain its CCR5-tropism but gain resistance to the drug
through specific mutations in the V3 loop of gp 120 that allow virus
binding in the presence of inhibitor (MacArthur and Novak, 2008).
This results in both an increase in IC 50
and a decrease in maximum
percent inhibition of virus replication for such viruses in vitro.
Absorption, Distribution, and Elimination. The oral bioavailability
of maraviroc, 23-33%, is dose dependent. Food decreases bioavailability
(AUC) as much as 50%, but there are no food requirements for
drug administration because clinical efficacy trials were conducted
without food restrictions. Maraviroc is 76% protein bound in human
plasma, with a volume of distribution of 194 L. Elimination is mainly
via CYP3A4 with an elimination t 1/2
of 10.6 hours (MacArthur and
Novak, 2008).
Untoward Effects. Maraviroc is generally well tolerated, with little
significant toxicity.
One case of serious hepatotoxicity with allergic features has
been reported, but in controlled trials significant (grade 3 or 4) hepatotoxicity
was no more frequent with maraviroc than with placebo.
There is a theoretical concern that CCR5 inhibition might interfere
with immune function; for example, humans with the Δ-32 genetic
deletion in CCR5 that prevents HIV-1 entry are also more likely to
develop severe West Nile virus encephalopathy (MacArthur and
Novak, 2008). However, to date there has been no obvious increase in
serious infections or malignancies with maraviroc treatment.
Precautions and Interactions. Maraviroc is a CYP3A4 substrate
and susceptible to pharmacokinetic drug interactions involving
CYP3A4 inhibitors or inducers. Recommended dosing of this
drug depends on concomitant medications. Maraviroc is not itself
a CYP inhibitor or inducer in vivo, although high-dose maraviroc
(600 mg daily) increased concentrations of the CYP2D6 substrate
debrisoquine.
Therapeutic Uses. Maraviroc (SELZENTRY) is approved
for use in HIV-infected adults who have baseline evidence
of predominantly CCR5-tropic virus. Maraviroc
is the only antiretroviral drug approved at three different
starting doses, depending on concomitant medications.
When combined with most CYP3A inhibitors,
the starting dose is 150 mg twice daily; when combined
with most CYP3A inducers, the starting dose is 600 mg
twice daily; for other concomitant medications, the
starting dose is 300 mg twice daily.
In phase 3 clinical trials involving heavily pretreated patients
with documented multidrug-resistant HIV-1, the addition of maraviroc
to optimized background therapy (OBT) resulted in an undetectable
(<50 copies/mL) plasma HIV-1 RNA in 44% of patients
after 24 weeks, compared to 17% with OBT alone; maraviroc-treated
patients also had higher mean CD4 lymphocyte count increases (120
versus 61 cells/mL). A maraviroc-based regimen was inferior to an
efavirenz-based regimen in one clinical trial in treatment-naive
patients (MacArthur and Novak, 2008). Maraviroc has little to no
efficacy in patients harboring CXCR4- or dual/mixed-tropic virus at