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

1640 generally can be avoided by separating administration of didanosine
from that of other agents by at least 2 hours after or 6 hours before the
interacting drug. The enteric-coated formulation of didanosine does
not alter ciprofloxacin or indinavir absorption.
Didanosine is excreted renally, and shared renal excretory
mechanisms provide a basis for drug interactions. Oral ganciclovir
can increase plasma didanosine concentrations approximately 2-fold
and may be associated with an increase in didanosine toxicity.
Allopurinol can increase the didanosine AUC more than 4-fold and
is contraindicated. Tenofovir increases the didanosine AUC by 44-
60% and also may increase the risk of didanosine toxicity. If these
two drugs must be given together, it is recommended to decrease the
didanosine dose from 400 to 250 mg once daily for patients >60 kg
(Chapman et al., 2003). Methadone decreases the didanosine AUC
by 57-63% (Rainey et al., 2000) possibly as a consequence of altered
GI motility and delayed absorption, although this has not been associated
with a higher risk of failing didanosine treatment.
Didanosine should be avoided in patients with a history of
pancreatitis or neuropathy because the risk and severity of both complications
increase. Co-administration of other drugs that cause pancreatitis
or neuropathy also will increase the risk and severity of
these symptoms. Ethambutol, isoniazid, vincristine, cisplatin, and
pentamidine also should be avoided.
The combination of didanosine and hydroxyurea was used to
exploit a beneficial interaction that creates a favorable intracellular
ratio of concentrations of dideoxyadenosine 5′-triphosphate to
deoxythymidine 5′-triphosphate (Frank et al., 2004). Although this
combination may boost didanosine antiviral activity modestly, it also
increases toxicity, producing peripheral neuropathy and fatal pancreatitis,
and should be avoided (Havlir et al., 2001).
Therapeutic Use. Didanosine (VIDEX, VIDEX EC) is FDAapproved
for adults and children with HIV infection in
combination with other antiretroviral agents. Didanosine
has long-term efficacy when combined with other nucleoside
analogs and HIV protease inhibitors or NNRTIs.
Didanosine as a component of combination therapy also
has beneficial effects in infants and children (Moreno
et al., 2007). However, this drug is no longer widely prescribed
in the developed world because of the availability
of other agents with less toxicity.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Zalcitabine
Zalcitabine (2′,3′-dideoxycytidine; ddC) is a synthetic cytidine analog
reverse transcriptase inhibitor that is designated as an orphan
drug for the treatment of advanced HIV infection. It is no longer
marketed because of toxicity (mainly peripheral neuropathy) and the
need for thrice daily dosing. It is active against HIV-1, HIV-2, and
hepatitis B virus (HBV). For additional information on this drug, see
the 11th edition of this book.
NON-NUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS
Non-nucleoside reverse transcriptase inhibitors
(NNRTIs) include a variety of chemical substrates that
bind to a hydrophobic pocket in the p66 subunit of the
HIV-1 reverse transcriptase. The NNRTI-binding
pocket is not essential for the function of the enzyme
and is distant from the active site. These compounds
induce a conformational change in the three-dimensional
structure of the enzyme that greatly reduces its
activity, and thus they act as noncompetitive inhibitors.
Unlike nucleoside and nucleotide reverse transcriptase
inhibitors, these compounds do not require intracellular
phosphorylation to attain activity. Because the binding
site for NNRTIs is virus-strain-specific, the approved
agents are active against HIV-1 but not HIV-2 or other
retroviruses and should not be used to treat HIV-2 infection
(Harris and Montaner, 2000). These compounds
also have no activity against host cell DNA polymerases.
The two most commonly used agents in this
category, efavirenz and nevirapine, are quite potent and
transiently decrease plasma HIV RNA concentrations
by two orders of magnitude or more when used as sole
agents (Havlir et al., 1995; Wei et al., 1995). The chemical
structures of the four approved NNRTIs are shown
in Figure 59–4, and their pharmacokinetic properties
are summarized in Table 59–3.
All approved NNRTIs are eliminated from the
body by hepatic metabolism. Nevirapine and delavirdine
are primarily substrates for CYP3A4, whereas
efavirenz is a substrate for CYPs 2B6 and 3A4, and
etravirine is subject to mixed metabolism. The steadystate
elimination half-lives of efavirenz and nevirapine
range from 24 to 72 hours, allowing daily dosing.
Efavirenz, etravirine, and nevirapine are moderately
potent inducers of hepatic drug-metabolizing enzymes
including CYP3A4, whereas delavirdine is mainly a
CYP3A4 inhibitor. Pharmacokinetic drug interactions
are thus an important consideration with this class of
compounds and represent a potential toxicity.
All NNRTIs except etravirine are susceptible to
high-level drug resistance caused by single-amino-acid
changes in the NNRTI-binding pocket (usually in
codons 103 or 181). Unlike nucleoside analogs or protease
inhibitors, efavirenz or nevirapine can induce
resistance and virologic relapse within a few days or
weeks if given as monotherapy (Wei et al., 1995).
Exposure to even a single dose of nevirapine in the
absence of other antiretroviral drugs is associated with
resistance mutations in up to one-third of patients
(Eshleman et al., 2004). These agents are potent and
highly effective but must be combined with at least two
other active agents to avoid resistance.
The use of efavirenz or nevirapine in combination with other
antiretroviral drugs is associated with favorable long-term suppression
of viremia and elevation of CD4+ lymphocyte counts (Sheran,
2005). Efavirenz in particular is a common component of first regimens