Trends in Parasitology
OpinionSimplified antimalarial therapeutic monitoring: using the day-7 drug level?
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).
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
References (26)
Clearance kinetics of parasites and pigment-containing leukocytes in severe malaria
Blood
(1996)A comparison of artesunate alone with combined artesunate and quinine in the parenteral treatment of acute falciparum malaria
Trans. R. Soc. Trop. Med. Hyg.
(2001)The relationship between capillary and venous concentrations of lumefantrine (benflumetol)
Trans. R. Soc. Trop. Med. Hyg.
(1998)Efficacy and effectiveness of dihydroartemisinin–piperaquine versus artesunate–mefloquine in falciparum malaria: an open-label randomised comparison
Lancet
(2006)How can we do pharmacokinetic studies in the tropics?
Trans. R. Soc. Trop. Med. Hyg.
(2001)- World Health Organisation (2006) Guidelines for the treatment of malaria, World Health Organization,...
- World Health Organisation (2002) Monitoring antimalarial drug resistance. Report of a WHO consultation,...
Assessment of the pharmacodynamic properties of the antimalarial drugs in vivo
Antimicrob. Agents Chemother.
(1997)Population pharmacokinetics of mefloquine in patients with acute falciparum malaria
Clin. Pharmacol. Ther.
(1999)Antimalarial drug resistance
J. Clin. Invest.
(2004)
Mathematical modelling of malaria chemotherapy: combining artesunate and mefloquine
Parasitology
Disposition of chloroquine in man after single intravenous and oral doses
Br. J. Clin. Pharmacol.
Population pharmacokinetics of piperaquine in adults and children with uncomplicated falciparum or vivax malaria
Br. J. Clin. Pharmacol.
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