PROBLEM STATEMENT:
•Both national and international treatment
guidelines for malaria currently recommend a dosage of 2.4mg/Kg BW artesunate
per dose by both IV and IM routes in adults and older children, and 3mg/Kg BW
per dose in children with body weights below 20Kg. Three doses are initially
administered over 24hrs at fixed times of 0hr, 12hr and 24hr, with repeat doses
given at 24hr intervals if necessary.
•Recommended dosage for IM artemether is
3.2mg/Kg BW as a bolus dose, with repeat doses of 1.6mg/Kg BW at intervals of
24hrs apart if necessary.
•The guidelines are however silent on the
maximum allowable doses for both of these drugs given by the parenteral routes,
resulting in a lack of consensus among healthcare practitioners on this
particular matter.
•This represents a classic example of
situations in medical practice when the carefully considered opinions of
individual practitioners are brought to bear in decision-making.
INDIRECT EVIDENCE:
•The current WHO Guidelines for malaria
(published on 14 March 2023) makes the following explicit recommendations on
the dosages of ACT antimalarial therapy by the oral route. Interest here is on
the artemisinin-derivative components of the medications.
•Oral artemether/lumefantrine
Up to a maximum of 80mg artemether BID (160mg
daily).
•Oral artesunate/amodiaquine
Up to a maximum of 200mg artesunate daily as a
single dose.
•Oral artesunate/mefloquine
Up to a maximum of 200mg artesunate daily as a
single dose.
•Oral artesunate/sulfadoxine-pyrimethamine
Up to a maximum of 200mg artesunate daily as a
single dose.
•Oral dihydroartemisinin/piperaquine
Up to a maximum of 200mg dihydroartemisinin
daily as a single dose.
PHARMACOKINETIC PRINCIPLES:
•Every drug exerts its actions within a
therapeutic window, bounded by both a minimum effective concentration [minimum
dose, Cmin.] and a maximum effective concentration [maximum dose, Cmax.].
•Increasing the dose of a drug above its Cmax
threshold increases the incidence and severity of toxic effects associated with
the drug, usually without producing any incremental benefits in the positive
therapeutic effects of the same drug.
•Moreover, the associated increments in the
cost of higher doses are not offset by any further benefits in treatment
outcomes, raising concerns about economics of healthcare and wastage of
resources.
•By reason of barriers to drug absorption from
the GI tract such as solubility and first-pass metabolism, bioavailability of
drugs after oral administration are almost always lower than levels achieved
after administration by any of the parenteral routes.
•Deductive arguments from the foregoing
principles are that, firstly, there should be a maximum allowable dose for both
artesunate and artemether when administered by the parenteral routes (only
perhaps this matter has not attracted
the attention of researchers yet), and secondly, both drugs when given by any
parenteral route should demonstrate at least equal potency at doses specified
in current guidelines as maximum daily oral dose for each drug.
QUESTIONS:
1. What are the maximum doses of IV/IM
artesunate and IM artemether in absolute terms?
The opinion of the author is as follows;
•IV/IM Artesunate, max. 200mg per dose
•IM Artemether, max. 160mg per dose
2. When is it appropriate to initiate oral ACT
after initial parenteral treatment?
On the basis of dosage frequency recommended
by current guidelines for parenteral artesunate or artemether, it is very
reasonable to recommend that oral ACT medications be initiated anytime around
24hrs after the last parenteral dose.
3. How safe is a switch to IV artesunate after
an initial IM artemether?
The PubChem monograph on Artemether depicts
that after IM administration artemether is detectable in plasma in appreciable
amounts by 1hr, and peak concentrations are established between 2-4hrs.
In situations when clinicians are considering that giving IV artesunate after an initial IM artemether is an emergency in order to achieve rapid clearance of heavy parasitaemia, the decision should depend mainly on elapsing time interval post IM artemether. Whereas giving IV artesunate within 1hr of IM artemether administration may be safe, the opinion of the author is that the estimated dose of artesunate should be reduced by a margin as a precaution to avoid occurrence of adverse effects. Administration of IV artesunate well after 1hr of IM artemether injection may not be necessary.
