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

efavirenz and nevirapine, and any patient who fails treatment with
this NNRTI should not be treated with those drugs.
Delavirdine is well absorbed, especially at pH<2. Antacids,
histamine H 2
-receptor antagonists, proton pump inhibitors, and
achlorhydria may decrease its absorption. Standard meals do not
alter the delavirdine AUC, and the drug can be administered irrespective
of food. The drug may have nonlinear pharmacokinetics
because the plasma t 1/2
increases with increasing doses (Scott and
Perry, 2000). Delavirdine clearance is primarily through oxidative
metabolism by CYP3A4, with <5% of a dose recovered unchanged
in the urine. At the recommended dose of 400 mg three times daily,
the mean elimination t 1/2
is 5.8 hours (range: 2-11 hours because of
the considerable interpatient variability in clearance).
As with all drugs in this class, the most common side effect
of delavirdine is rash, which occurs in 18-36% of subjects. Rash
usually is seen in the first few weeks of treatment and often
resolves despite continued therapy. Severe dermatitis, including
erythema multiforme and Stevens-Johnson syndrome, has been
reported but is rare. Elevated hepatic transaminases and hepatic
failure also have been reported. Neutropenia also may occur rarely
(Scott and Perry, 2000).
Delavirdine is both a substrate for and an inhibitor of
CYP3A4 and can alter the metabolism of other CYP3A4 substrates.
Potent inducers of CYP3A4, such as carbamazepine, phenobarbital,
phenytoin, rifabutin, and rifampin, may decrease delavirdine concentrations
and should be avoided. Delavirdine increases the
plasma concentrations of most HIV protease inhibitors (Scott and
Perry, 2000).
Initial monotherapy studies with delavirdine produced only
transient decreases in plasma HIV RNA concentrations owing to
rapid emergence of resistance. Later studies of delavirdine in combination
with nucleoside analogs showed sustained decreases in
HIV-1 RNA.
HIV PROTEASE INHIBITORS
HIV protease inhibitors are peptide-like chemicals
that competitively inhibit the action of the virus
aspartyl protease (Figure 59–5). This protease is a
homodimer consisting of two 99-amino acid
monomers; each monomer contributes an aspartic acid
residue that is essential for catalysis (Flexner, 1998).
The preferred cleavage site for this enzyme is the N-
terminal side of proline residues, especially between
phenylalanine and proline. Human aspartyl proteases
(i.e., renin, pepsin, gastricsin, and cathepsins D and
E) contain only one polypeptide chain and are not significantly
inhibited by HIV protease inhibitors.
These drugs prevent proteolytic cleavage of HIV gag and pol
precursor polypeptides that include essential structural (p17, p24,
p9, and p7) and enzymatic (reverse transcriptase, protease, and integrase)
components of the virus. This prevents the metamorphosis of
HIV virus particles into their mature infectious form (Flexner, 1998).
Infected patients treated with HIV protease inhibitors as sole agents
experienced a 100- to 1000-fold mean decrease in plasma HIV RNA
concentrations within 12 weeks, an effect similar in magnitude to
that produced by NNRTIs (Ho et al., 1995).
The pharmacokinetic properties of HIV protease
inhibitors are characterized by high interindividual variability,
which may reflect differential activity of intestinal
and hepatic CYPs (Flexner, 1998). Clearance is
mainly through hepatic oxidative metabolism. All
except nelfinavir are metabolized predominantly by
CYP3A4 (and nelfinavir’s major metabolite is cleared
by CYP3A4). Elimination half-lives of the HIV protease
inhibitors range from 1.8 to 10 hours (Table 59–4), and
most of these drugs can be dosed once or twice daily.
Most HIV protease inhibitors are highly protein bound
in plasma, and adding plasma proteins will increase their
in vitro IC 50
(Molla et al., 1998). Fractional penetration
into the CSF is also low for most of these agents,
although the clinical significance is unknown.
An important toxicity common to all approved
HIV protease inhibitors is the potential for metabolic
drug interactions. Most of these drugs inhibit CYP3A4
at clinically achieved concentrations, although the magnitude
of inhibition varies greatly, with ritonavir by far
the most potent (Piscitelli and Gallicano, 2001). It is
now a common practice to combine HIV protease
inhibitors with a low dose of ritonavir to take advantage
of that drug’s remarkable capacity to inhibit
CYP3A4 metabolism (Flexner, 2000).
Although the approved dose of ritonavir for antiretroviral
treatment is 600 mg twice daily, doses of 100 or 200 mg once or
twice daily are sufficient to inhibit CYP3A4 and increase (“boost”)
the concentrations of most concurrently administered CYP3A4 substrates.
Lower doses of ritonavir are much better tolerated. The
enhanced pharmacokinetic profile of HIV protease inhibitors administered
with ritonavir reflects inhibition of both first-pass and systemic
clearance, resulting in improved oral bioavailability and a
longer elimination t 1/2
of the co-administered drug. This allows a
reduction in both drug dose and dosing frequency while increasing
systemic concentrations (Flexner, 2000). Combinations of darunavir,
lopinavir, fosamprenavir, and atazanavir with ritonavir are approved
for once-daily administration.
Most HIV protease inhibitors are substrates for
the P-glycoprotein efflux pump (P-gp) (Chapter 5).
P-gp in capillary endothelial cells of the blood-brain barrier
limits the penetration of HIV protease inhibitors into the brain
(Kim et al., 1998), although the low CSF-to-plasma drug concentration
ratio characteristic of these drugs also may reflect extensive
binding to plasma proteins. Most HIV protease inhibitors
penetrate less well into semen than do nucleoside reverse transcriptase
inhibitors and NNRTIs. Virologic responses in plasma, CSF,
and semen usually are concordant (Taylor et al., 1999), and the
clinical significance of P-gp and protein-binding effects is unclear.
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CHAPTER 59
ANTIRETROVIRAL AGENTS AND TREATMENT OF HIV INFECTION