Use of quantitative pharmacology tools to improve malaria treatments

ABSTRACT

The use of pharmacokinetic (PK) and pharmacodynamic (PD) data to inform antimalarial treatment regimens has accelerated in the past few decades, due in no small part to the stimulus provided by progressive development of parasite resistance to most of the currently available drugs. An understanding of the disposition, interactions, efficacy and toxicity of the mainstay of contemporary antimalarial treatment, artemisinin combination therapy (ACT), has been facilitated by PK/PD studies which have been used to refine treatment regimens across the spectrum of disease, especially in special groups including young children and pregnant women. The present review highlights recent clinically-important examples of the ways in which these quantitative pharmacology tools have been applied to improve ACT, as well as 8-aminoquinoline use and the characterisation of novel antimalarial therapies such as the spiroindolones.

KEYWORDS:

• Malaria
• treatment
• pharmacokinetic
• pharmacodynamic
• artemisinin
• resistance

Financial & competing interests disclosure

T M E Davis is supported by a National Health and Medical Research Council (NHMRC) Practitioner Fellowship (#1058260). B R Moore is supported by a NHMRC Early Career Fellowship (#1036951).

T M E Davis has served on advisory boards for, and received research funding from, Suda Ltd, manufacturers of the sublingual artemether formulation ArtiMist®. S Salman has also received research funding from Suda Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. None of the other authors have a potential conflict of interest to report.

Key issues

• The progressive development of resistance of malaria parasites to conventional antimalarial drugs, starting with CQ in the 1950s, has led to the widespread adoption of artemisinin combination therapy (ACT) as first-line treatment for uncomplicated malaria and of parenteral artesunate for severe disease.

• At the same time, there has been an increasing recognition of the need for pharmacokinetic (PK) and pharmacodynamic (PD) characterization of antimalarial drugs and their combinations so that rational dosing regimens are developed that prevent undertreatment and minimize toxicity.

• This initiative has been facilitated by improved drug assay methodology, more convenient sampling schedules, robust population PK/PD modeling and simulation techniques, and pooling of available data from a variety of geo-epidemiological situations.

• These quantitative pharmacology tools have identified patient groups, such as young children and pregnant women, who may need increased mg/kg doses of ACT components.

• PK/PD studies and have also helped characterize clinically important drug interactions such as when ACT is prescribed for HIV-infected patients on anti-retroviral therapy (ART), including situations in which coadministered ACT and ART reduce the risk of recurrent malaria.

• Primaquine is the only drug currently available for radical cure of vivax malaria and PK/PD studies are being used to determine whether the course of treatment can be abbreviated safely and without loss of efficacy.

• Tafenoquine, an alternative to primaquine in late-stage clinical development, could prove more effective than primaquine but its relatively long half-life raises the potential for prolonged toxicity.

• Given that artemisinin resistance or tolerance has emerged in recent years, there is a need for alternative rapidly acting schizonticidal drugs of which the spiroindolones appear the most promising.

• Optimized antimalarial pharmacotherapy should not lessen the need for other malaria control measures such as prompt and effective diagnosis and vector reduction measures.