Pharmacokinetic studies of antimalarials: recent developments

Abstract

Pharmacokinetic studies are essential for the development of safe and effective antimalarial treatment regimens, but there are clinical situations in which there are limited data on drug disposition. These include very young children, pregnant women, and where drug interactions may alter treatment response. New approaches such as sampling methods involving low volumes and minimal preparation such as dried blood spots, highly sensitive and specific multidrug assays, and population PK analyses which can evaluate the influence of covariates such as age, pregnancy and coadministered therapies, can generate robust data that inform treatment in the most challenging situations in the tropics.

Keywords:

• Children
• interactions
• malaria
• pharmacokinetics
• pregnancy

The importance of pharmacokinetic (PK) studies of antimalarial drugs in the development of safe and effective treatment regimens has been stressed in recent reviews.[1–3] In particular, the characterization of drug disposition of dual antimalarial combinations, the contemporary therapeutic gold standard, is vital in achieving an optimal ‘target product profile’.[1] The history of antimalarial therapy is littered with drugs to which the Plasmodium parasite has developed resistance, in part because of a lack of dose optimization based on robust PK studies specific to the epidemiological situations in which the drugs are deployed.[3] Relevant contemporary examples of areas in which novel PK data could inform management of malaria infections are infancy, pregnancy and when interactions between the component drugs themselves and with coadministered drugs for other diseases have the potential to influence outcome.

The burden of malaria in infants <6 months of age may be higher than previously thought.[4] Children in this age-group can have few symptoms and low parasitemias because of the protective effect of maternal antibodies,[5] but anemia and other serious complications can develop if diagnosis and treatment are delayed.[6,7] There are few data relating to the safety, disposition and efficacy of artemisinin combination therapy (ACT), the treatment considered most appropriate for this age group.[4,8] This includes the debated issue of artemisinin-associated neuroaudiotoxicity.[9] Young children generally require higher mg/kg doses than adults,[10] but PK studies in the youngest age-groups would also need to take into account the immaturity of hepatic drug metabolizing systems which could prolong elimination and lead to drug accumulation and potential toxicity especially during the first 6 weeks of life.[11] In addition, assay of antimalarial drugs in young infants is problematic given that the recommended maximum sample blood volume is ≤8 ml/kg over 8 weeks.[12]

The measurement of drug concentrations in small volume dried blood spots (DBS) represents a novel way of overcoming this latter limitation. Small blood volumes (10–20 µl) can be taken serially on filter paper which can usually be stored and transported at room temperature. A small disc (chad) is subsequently punched out from the filter paper, and the drug eluted and assayed. This strategy is ideally suited to PK studies of neonates and young children in developing countries by DBS sampling from heel or earlobe pricks, or through venous access devices, as has been done in the case of antibiotics.[13,14] The main disadvantages are time-dependent intracellular drug compartmentalization and metabolism, and loss of sensitivity at low concentrations. In the case of ACT, these factors can be minimized by the use of blood matrix stabilizers,[15] and sensitive assay methods such as liquid chromatography–mass spectrometry which would allow quantification of multiple drugs and active metabolites in the one sample from an ACT-treated child.[16]

Although malaria can have devastating effects on pregnant women and their unborn babies, pregnant women have usually been excluded from PK studies of antimalarial drugs because of fears of adverse maternal and fetal outcomes.[17] In the case of ACT, most of the components have been developed in China based on preclinical and clinical studies that have generated limited data on drug disposition and safety in pregnancy. There is evidence that artemisinin drugs are embryotoxic,[18] but recent human PK and intervention studies of ACT given in late pregnancy have shown both safety and efficacy.[17] Ideally, ACT component drugs should be assessed rigorously in reproductive toxicity studies in animals before they are recommended for pregnant women, as has been done in the case of the widely used artemisinin partner drug piperaquine.[19]

Conventional adult antimalarial drug doses are recommended in pregnancy, but there is evidence that pregnancy per se, malaria infection and race/ethnicity can alter the PK properties of ACT components.[20,21] Whether these factors adversely alter treatment outcome are unknown but relatively large-scale effectiveness and epidemiological studies would be required to provide the answer. There are also relatively few studies of the transfer of antimalarial drugs into breast milk. It is possible that DBS sampling of breast-fed infants could complement analyses of breast milk concentrations,[22] thus providing a comprehensive assessment of the potential neonatal antimalarial efficacy and toxicity of maternal antimalarial treatment.

Primaquine is an antimalarial drug used primarily for radical cure of vivax malaria through elimination of hepatic hypnozoites after treatment of asexual forms. There is evidence that this effect relies on generation of short-lived phenolic metabolites through the activity of the cytochrome P450 enzyme 2D6.[23] Lumefantrine, which is combined with artemether in the most commonly prescribed ACT, is a known 2D6 inhibitor. Starting a conventional 2-week primaquine course straight after the last dose of this form of ACT to prevent relapse of Plasmodium vivax could, therefore, attenuate its efficacy. A further example of a potentially important interaction involving antimalarial therapy is in patients with HIV infection who are treated with artemether-lumefantrine for intercurrent malaria. Protease inhibitors may increase exposure to lumefantrine and decrease plasma concentrations of artemether and its active metabolite dihydroartemisinin in this situation, while non-nucleoside reverse transcriptase inhibitors can decrease exposure to all three compounds.[24] These effects are mediated through induction or inhibition of components of the cytochrome P450 enzyme system. Further studies are needed to establish the clinical importance of all these various interactions.

With the increasing use of highly sensitive and specific drug assay methodology, population PK analyses which can evaluate the influence of covariates such as age, pregnancy and coadministered therapies, and sampling methods that can be used successfully in challenging situations such as in very young children in remote health care facilities, the prospects for improvements in the management of malaria informed by robust PK studies are bright.

Financial & competing interests disclosure

T Davis is supported by a National Health and Medical Research Council of Australia Practitioner Fellowship. The author has 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.