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

failures are rare. However, when atovaquone-proguanil treatment fails
because of parasite resistance, the recurrent malarial attack commonly
occurs ~20-30 days after treatment initiation. Treatment with different
drugs should then be started. Earlier treatment failures (during
the first 2 weeks after treatment initiation) are more likely related to
lack of compliance or inadequate drug levels (Musset et al., 2006;
Rose et al., 2008).
Absorption, Fate, and Excretion. Atovaquone absorption after a single
oral dose is slow, erratic, and variable due to its highly lipophilic
nature and low aqueous solubility. Absorption improves when the
drug is taken with a fatty meal (Boggild et al., 2007). More than 99%
of the drug is bound to plasma protein, and cerebrospinal fluid levels
are <1% of those in plasma. Profiles of drug concentration versus
time often show a double peak, albeit with considerable
variability. The first peak appears in 1-8 hours, whereas the second
occurs 1-4 days after a single dose. This pattern suggests an enterohepatic
circulation. In the absence of a CYP-inducing second medication,
humans do not metabolize atovaquone significantly. The
drug is excreted in bile, and >94% of the drug is recovered
unchanged in feces; only traces appear in the urine. Atovaquone has
a reported elimination t 1/2
from plasma of 2-3 days in adults and 1-2 days
in children. Clearance is unaffected by dose or co-administration of
proguanil (Boggild et al., 2007).
Therapeutic Uses. Atovaquone-proguanil is used for
malaria chemoprophylaxis in adults and children ≥11 kg
and for treatment of uncomplicated P. falciparum malaria
in adults and children ≥5 kg.
A tablet containing a fixed dose of 250 mg atovaquone and
100 mg proguanil hydrochloride, taken orally, is highly effective and
safe in a 3-day regimen for treating mild-to-moderate attacks of
chloroquine- or sulfadoxine-pyrimethamine-resistant P. falciparum
malaria (Looareesuwan et al., 1999). Although the same regimen
followed by a primaquine course is effective in treatment of P. vivax
malaria (Lacy et al., 2002), evidence for atovaquone-proguanil efficacy
as treatment of non–P. falciparum malaria is limited (Boggild
et al., 2007). The CDC does not recommend the combination for
non-P. falciparum treatment, except for malaria caused by chloroquineresistant
P. vivax. Atovaquone-proguanil is a standard agent for
malaria chemoprophylaxis. It can be discontinued 1 week after leaving
the endemic area because both components are active against
liver stage parasites. Experience in prevention of non–P. falciparum
malaria is also limited (Ling et al., 2002). P. vivax infection may
occur after drug discontinuation, indicating imperfect activity against
exo-erythrocytic stages of this parasite.
Toxicity. Atovaquone may cause side effects (abdominal pain, nausea,
vomiting, diarrhea, headache, rash) that require cessation of
therapy. Vomiting and diarrhea may decrease drug absorption, resulting
in therapeutic failure. However, readministration of this drug
within an hour of vomiting may still be effective in patients with
P. falciparum malaria. Atovaquone occasionally causes transient elevations
of serum transaminase or amylase.
Precautions and Contraindications. Although atovaquone is generally
considered to be safe, it needs further evaluation in children <11 kg,
pregnant women, and lactating mothers. Accordingly, although the
drug is not formally recommended for these individuals, the risks and
benefits of its use (both as chemoprophylaxis and treatment) should
be considered carefully for individual patients, taking known toxicities
into account. Preclinical evaluations for carcinogenicity, mutagenicity,
and teratogenicity have been negative. Atovaquone may
compete with certain drugs for binding to plasma proteins, and therapy
with rifampin, a potent inducer of CYP-mediated drug metabolism,
can reduce plasma levels of atovaquone substantially, whereas
atovaquone may raise plasma levels of rifampin. Co-administration
with tetracycline is associated with a 40% reduction in plasma concentration
of atovaquone.
DIAMINOPYRIMIDINES
History. Based on their structural analogy with the antimalarial
proguanil (see section on proguanil), large
numbers of 2,4-diaminopyrimidines were tested for
inhibitory activity against malarial parasites, leading to
the identification of the potent antimalarial agent
pyrimethamine. Studies also observed marked antimalarial
synergy between sulfonamides and proguanil.
Accordingly, pyrimethamine was formulated and marketed
as a fixed combination with sulfadoxine, a sulfonamide
with pharmacokinetics that match those of
pyrimethamine. For several decades sulfadoxinepyrimethamine
(FANSIDAR) has been a primary treatment
for uncomplicated P. falciparum malaria,
especially against chloroquine-resistant strains, but
widespread resistance now seriously compromises its
efficacy and it is no longer recommended for the treatment
of uncomplicated malaria.
Mechanisms of Antimalarial Action and Resistance.
Pyrimethamine is a slow-acting blood schizontocide
with antimalarial effects in vivo similar to those of
proguanil, resulting from inhibition of folate biosynthesis
in Plasmodium. However, pyrimethamine has
greater antimalarial potency, and its t 1/2
is much longer
than that of cycloguanil, the active metabolite of
proguanil. The efficacy of pyrimethamine against
hepatic forms of P. falciparum is less than that of
proguanil, and at therapeutic doses pyrimethamine fails
to eradicate P. vivax hypnozoites or gametocytes of any
Plasmodium species. It increases the number of circulating
P. falciparum mature infecting gametocytes, likely
leading to increased transmission to mosquitoes during
the period of treatment.
1399
CHAPTER 49
CHEMOTHERAPY OF MALARIA