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

1396 site. Both artesunate and artemether have modest levels of plasma protein
binding, ranging from 43% to 82%. These derivatives are extensively
metabolized and converted to dihydroartemisinin, which has a
plasma t 1/2
of 1-2 hours (German and Aweeka, 2008). Rectal administration
of artesunate has emerged as an important administration
route, especially in tropical countries where it can be lifesaving.
However, drug bioavailability via rectal administration is highly variable
among individual patients (Medhi et al., 2009).
With repeated dosing, artemisinin and artesunate induce their
own CYP-mediated metabolism, primarily via CYPs 2B6 and 3A4.
This may enhance clearance by up to 5-fold. Recent studies have
found no clinically significant pharmacokinetic or toxic interactions
between artemisinins and its partner drugs.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Therapeutic Uses. Given their rapid and potent activity
against even multidrug-resistant parasites, the
artemisinins are valuable for the treatment of severe
P. falciparum malaria. Intravenous artesunate is more
than comparable to a standard quinine regimen, likely
possessing higher efficacy and a better safety profile in
many patient populations (Rosenthal, 2008). The
artemisinins generally are not used alone because of
their limited ability to eradicate infection completely.
In numerous studies in Africa, South America, and
Asia, artemisinins have proven highly effective, when
combined with other antimalarials, for the first-line
treatment of malaria (Sinclair et al., 2009). Artemisinins
should not be used for chemoprophylaxis because of
their short t 1/2
, which translates into high recrudescence
rates. In the U.S., the Food and Drug Administration
(FDA) has approved the use of artemether-lumefantrine
for oral treatment of uncomplicated P. falciparum
malaria. Although useful in treating presumptively
chloroquine-resistant P. vivax, artemether-lumefantrine
does not have a formal FDA-approved indication for
this infection. Under an investigational new drug (IND)
application, intravenous artesunate is now indicated for
the treatment of severe malaria; this drug currently can
be obtained through the Centers for Disease Control
and Prevention (CDC) Drug Service or CDC
Quarantine Stations.
Toxicity and Contraindications. The increasing usage of ACTs has
focused attention on the safety profile of artemisinins, especially
with regard to potential toxic effects in infants and during the first
trimester of pregnancy. In pregnant rats and rabbits, artemisinins can
cause increased embryo lethality or malformations early postconception.
Preclinical toxicity studies have identified the brain (and
brainstem), liver, bone marrow, and fetus as the principal target
organs. In patients, the many neurological changes that accompany
severe malaria confound the evaluation of drug neurotoxicity; however,
no systematic neurological changes were attributable to treatment
in patients >5 years of age. As in small animals, patients may
develop dose-related and reversible decreases in reticulocyte and
neutrophil counts and increases in transaminase levels in patients.
About 1 in 3000 patients develops an allergic reaction. Studies of
artemisinin treatment during the first trimester have found no evidence
of adverse effects on fetal development (Eastman and Fidock,
2009). Nonetheless, out of general concern, it is recommended that
ACTs not be used for the treatment of children ≤5 kg or during the
first trimester of pregnancy.
ACT Partner Drugs. The short plasma t 1/2
of artemisinin
and its derivatives translates into substantial treatment
failure rates when artemisinins are used as monotherapy.
Combining an artemisinin derivative with a longerlasting
partner drug assures sustained antimalarial
activity. Current ACT regimens that are well tolerated
in adults and children ≥5 kg include artemetherlumefantrine,
artesunate-mefloquine, artesunate-amodiaquine,
artesunate-sulfoxadine-pyrimethamine, and
dihydroartemisinin-piperaquine. Artesunate-pyronaridine
has also recently completed phase III clinical trials.
Combination with mefloquine or sulfadoxinepyrimethamine
is discussed in a separate section.
Properties of other partner drugs are discussed later.
Lumefantrine shares structural similarities with the
arylaminoalcohol drugs mefloquine and halofantrine
(Figure 49–2) and is formulated with artemether
(COARTEM).
This combination has proven to be highly effective for the
treatment of uncomplicated malaria and is the most widely used firstline
antimalarial across Africa. The pharmacokinetic properties of
lumefantrine include a large apparent volume of distribution and a terminal
elimination t 1/2
of 4-5 days. Human pharmacokinetic and pharmacodynamic
studies correlate the risk of clinical failure (the
likelihood to recrudesce) with plasma lumefantrine concentrations
falling below 280 ng/mL. These findings, combined with a report of
up to 15-fold variability in lumefantrine plasma concentrations in clinical
trial volunteers, highlight the importance of appropriate dosing
with lumefantrine-containing combinations (Checchi et al., 2006).
Administration with a high-fat meal is recommended because it significantly
increases absorption. Recently a sweetened dispersible
formulation of artemether-lumefantrine (COARTEM Dispersible) has
been approved for treatment of children. This formulation has
comparable pharmacokinetics to crushed tablets and provides substantially
improved ease of administration.
Amodiaquine is a congener of chloroquine
(Figure 49–2) that is no longer recommended in the
U.S. for chemoprophylaxis of P. falciparum malaria
because of its toxicity (hepatic and agranulocytosis).
These adverse events, however, were generally associated
with its prophylactic use. A meta-analysis of clinical
studies found that therapeutic amodiaquine
regimes, with a total dose of up to 35 mg/kg body
weight administered over 3 days, were as well tolerated
as chloroquine for the treatment of uncomplicated P.
falciparum malaria (Olliaro and Mussano, 2003). One