Trends in Parasitology
Volume 24, Issue 4, April 2008, Pages 159-163
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Simplified antimalarial therapeutic monitoring: using the day-7 drug level?

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The blood concentration profiles of most antimalarial drugs vary considerably between patients. The interpretation of antimalarial drug trials evaluating efficacy and effectiveness would be improved considerably if the exposure of the infecting parasite population to the antimalarial drug treatment could be measured. Artemisinin combination treatments are now recommended as first-line drugs for the treatment of falciparum malaria. Measurement of the blood, serum or plasma concentration of the slowly eliminated partner antimalarial drug on day 7 of follow-up is simpler and might be a better determinant of therapeutic response than the area under the concentration–time curve. Measurement of the day-7 drug level should be considered as a routine part of antimalarial drug trials.

Section snippets

Antimalarial efficacy assessments

Behavioural, pharmacokinetic (PK) (see Glossary) and pharmacodynamic (PD) factors might all contribute to treatment failure (i.e. the failure to clear parasitaemia or the subsequent recrudescence of infection) following the administration of antimalarial drugs. In treating uncomplicated malaria, one or more of the following factors could be responsible for treatment failure: (i) low-quality drugs; (ii) incorrect or inadequate dosing; (iii) poor adherence (behavioural); (iv) vomiting and reduced

Assessing responses to combination treatments

When blood concentrations of antimalarial drugs exceed the minimum parasiticidal concentration (MPC) for the infecting parasites, there is a fixed fractional reduction in parasite number each asexual cycle (first-order kinetics). As concentrations fall below the MPC, the fractional reduction decreases until there is no inhibition of multiplication 3, 4. The blood concentration at which the multiplication factor per cycle is 1 can be called the minimum inhibitory concentration (MIC). Cure from

Antimalarial pharmacodynamics

Even the most potent antimalarials – the artemisinin derivatives, which, at concentrations above the MPC, reduce parasite numbers ∼10 000-fold per asexual parasite cycle (corresponding to a 99.99% reduction) – cannot clear all of the parasites from the entire blood volume in two asexual cycles (four days) 3, 7, 8. Three-day regimens expose two asexual cycles to the artemisinin derivative [3]. If the maximum total parasite biomass possible in an adult patient is ∼1013 parasites, following

Antimalarial pharmacokinetics

Although several antimalarials have multiphasic elimination profiles, most are in the exponential (i.e. log–linear) terminal elimination phase (sometimes termed β phase) seven days after the start of drug administration (i.e. the fourth day after finishing a three-day ACT course). The AUC after day 7 is obtained by dividing the blood or plasma concentration at this time (C7) by the first-order terminal elimination rate constant (ke) (Equation 1).AUC7=C7/ke

The AUC7−∞ is easier to characterize

Melding pharmacokinetics and pharmacodynamics

As the initial therapeutic responses following ACTs are determined primarily by the artemisinin component, the plasma concentrations of the partner drug during the first three days of treatment are relevant mainly because: (i) they are needed to kill any spontaneously arising artemisinin-resistant mutant parasites (i.e. resistance prevention); and (ii) they determine the blood concentrations after three days that will eradicate the residual parasites after artemisinin treatment (a maximum of 100

Sampling methods for monitoring in vivo responses to antimalarial drugs

In vivo responses to antimalarial drugs must be monitored on a regular basis to ensure that cure rates are adequate and to provide an early warning of the development of resistance [2]. Antimalarial treatment is reliably efficacious only if antimalarial drug concentrations in the blood are adequate. Treatment failure results from inadequate blood concentrations of the drug or from resistance (i.e. inadequate drug activity), or both. In the past, the measurement of antimalarial drugs in blood,

Informing policy and practice

The efficacy and safety of ACTs and their successors should be monitored regularly to inform policy recommendations. Because treatment failure results from low blood concentrations of the antimalarial drug, from resistance or from both, it is important that drug exposure be assessed. With the exception of P. malariae and Plasmodium knowlesi infections, the day-7 antimalarial blood level is a measure of parasite exposure in the fourth asexual cycle after the start of treatment. Blood levels of

Concluding remarks and future directions

The interpretation of results from antimalarial drug trials, and the optimization of drug dosage would be facilitated by measuring individual drug exposure. However, taking multiple samples in large numbers of treated patients is seldom feasible. Routine measurement of day-7 antimalarial drug levels could considerably improve the assessment of both efficacy and effectiveness. The value of this simple measurement should be compared with more-complex PK parameters in both retrospective and

Acknowledgements

We are grateful to Liz Ashley, Niklas Lindegardh, Nick Day and Francois Nosten for their considerable input into this work. This work was part of the Mahidol–Oxford Tropical Medicine Research Unit activities supported by the Wellcome Trust.

Glossary

ACT
artemisinin-based combination treatment – a combination of artemisinin or derivative (usually artesunate, dihydroartemisinin or artemether) given for three days with a more slowly eliminated antimalarial drug.
AUC
the area under the whole-blood, serum or plasma concentration–time curve.
Distribution phase
the phase following drug administration during which the drug distributes to and exchanges with the tissues. During this phase, blood concentrations fall faster than during the elimination

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