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

1652 diarrhea, nausea, and vomiting. These are less frequent and less
severe than those reported with the 600 mg twice-daily standard dose
of ritonavir but more common compared to those of boosted
atazanavir and darunavir. The most common laboratory abnormalities
include elevated total cholesterol and triglycerides. Because the
same adverse effects occur with ritonavir, it is unclear whether these
side effects are due to ritonavir, lopinavir, or both.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Precautions and Interactions. Because lopinavir metabolism is
highly dependent on CYP3A4, concomitant administration of agents
that induce CYP3A4, such as rifampin, may lower plasma lopinavir
concentrations considerably. St. John’s wort is a known inducer of
CYP3A4, leading to lower concentrations of lopinavir and possible
loss of antiviral effectiveness. Co-administration of other antiretrovirals
that can induce CYP3A4, including amprenavir, nevirapine or
efavirenz, may require increasing the dose of lopinavir (Oldfield and
Plosker, 2006).
Although lopinavir is a weak inhibitor of CYP3A4 in vitro, the
ritonavir in the co-formulated capsule strongly inhibits CYP3A4 activity
and probably dwarfs any lopinavir effect. The liquid formulation of
lopinavir contains 42% ethanol and should not be administered with
disulfiram or metronidazole (Chapter 23). Ritonavir is also a moderate
CYP inducer at the dose employed in the co-formulation and can
adversely decrease concentrations of some co-administered drugs (e.g.,
oral contraceptives). There is no direct proof that lopinavir is a CYP
inducer in vivo; however, concentrations of some co-administered drugs
(e.g., amprenavir and phenytoin) are lower with the lopinavir/ritonavir
co-formulation than would have been expected with low-dose ritonavir
alone (Oldfield and Plosker, 2006).
Therapeutic Use. In comparative clinical trials, lopinavir
has antiretroviral activity at least comparable with that
of other potent HIV protease inhibitors and better than
that of nelfinavir. Lopinavir also has considerable and
sustained antiretroviral activity in patients who failed
previous HIV protease inhibitor–containing regimens.
In one study, 70 subjects who had failed therapy with one
previous HIV protease inhibitor were treated for 2 weeks with
lopinavir, followed by the addition of nevirapine. At 48 weeks, 60%
of subjects had plasma HIV-1 RNA levels of <50 copies/mL despite
substantial phenotypic resistance to other HIV protease inhibitors
(Oldfield and Plosker, 2006). Because plasma concentrations of
lopinavir generally are much higher than those required to suppress
HIV replication in vitro, the drug may be capable of suppressing
HIV isolates with low-level protease inhibitor resistance.
The adult lopinavir/ritonavir dose is 400/100 mg (two tablets)
twice daily, or 800/200 mg (four tablets) once daily, with or without
food. Lopinavir/ritonavir should not be dosed once daily in treatment-experienced
patients. Lopinavir/ritonavir is approved for use in
pediatric patients ≥14 days, with dosing based on either weight or
body surface area. A pediatric tablet formulation is available for use
in children >6 months of age.
Atazanavir
Chemistry and Antiviral Activity. Atazanavir is an azapeptide
protease inhibitor with a C 2
-symmetrical
chemical structure that is active against both HIV-1 and
HIV-2 (Croom et al., 2009) (Figure 59–6). The IC 50
for
HIV-1 in various in vitro assays ranges from 2 to 15 nM.
In the presence of 40% human serum, the in vitro IC 50
is increased 3- to 4-fold (Croom et al., 2009).
Mechanisms of Resistance. The primary atazanavir
resistance mutation occurs at HIV protease codon 50
and confers abut a 9-fold decreased susceptibility. This
isoleucine-to-leucine substitution (I50L) is distinct
from the isoleucine-to-valine substitution selected by
fosamprenavir and darunavir.
This mutation was present in 100% of viruses isolated from
patients failing therapy in one clinical trial (Croom et al., 2009).
Isolates with only this mutation are still susceptible to inhibition by
other protease inhibitors. Sensitivity to atazanavir is affected by various
primary and secondary mutations that accumulate in patients
who have failed other HIV protease inhibitors, with high-level resistance
more likely if five or more additional mutations are present
(Croom et al., 2009).
Absorption, Distribution, and Elimination. Atazanavir is absorbed
rapidly after oral administration, with peak concentrations occurring
~2 hours after dosing. Atazanavir absorption is sensitive to food: a
light meal increases the AUC by 70%, whereas a high-fat meal
increases the AUC by 35% (Croom et al., 2009). It is therefore recommended
that the drug be administered with food, which also
decreases the interindividual variability in pharmacokinetics, unless
given with ritonavir. Absorption is pH dependent, and proton pump
inhibitors or other acid-reducing agents substantially reduce
atazanavir concentrations after oral dosing; this effect is only partially
reversed by concomitant ritonavir.
Atazanavir undergoes oxidative metabolism in the liver primarily
by CYP3A4, which accounts for most of the elimination of
this drug. Only 7% of the parent drug is excreted unchanged in the
urine. The mean elimination t 1/2
of atazanavir at the standard 400-mg
once-daily dose is ~7 hours; however, the drug has nonlinear pharmacokinetics,
and the t 1/2
increases to nearly 10 hours at a dose of
600 mg (Croom et al., 2009). Atazanavir is 86% bound to plasma
proteins, both to albumin and α 1
-acid glycoprotein. It is present in
CSF at <3% of plasma concentrations but has excellent penetration
into seminal fluid (Croom et al., 2009).
Untoward Effects. Like indinavir, atazanavir frequently causes
unconjugated hyperbilirubinemia, although this is mainly a cosmetic
side effect and not associated with hepatotoxicity.
Approximately 40% of subjects receiving 400 mg atazanavir
once daily in initial clinical trials developed a significant increase in
total bilirubin (Croom et al., 2009), although only 5% developed jaundice.
This is a consequence of inhibition of UDP-glucuronosyl transferase
by atazanavir, and the side effect occurs more prominently in
those who are genetically deficient in this enzyme, e.g., patients with
Gilbert’s syndrome (Rotger et al., 2005). Postmarketing reports
include hepatic adverse reactions of cholecystitis, cholelithiasis,
cholestasis, and other hepatic function abnormalities.
Other side effects reported with atazanavir include diarrhea
and nausea, mainly during the first few weeks of therapy. Overall,