The contribution of clinical pharmacology to antimalarial drug discovery and development

Abstract

Unlike human immunodeficiency virus (HIV) disease or tuberculosis, both of which are also major threats to public health throughout the tropics, uncomplicated falciparum malaria is relatively cheaply and rapidly cured, usually in Outpatients. However, in common with both HIV and TB (but to varying degrees), control of malaria is threatened by inadequate resources and drug resistance. Worldwide, it is Africa that carries the greatest burden of falciparum malaria mortality and morbidity; by no coincidence, it is also Africa that is most resource-limited. The drugs for severe disease (quinine and the artemisinins) are largely unaffected by resistance so far, but the ‘first-line’ drugs, mostly used by outpatients (mainly chloroquine and sulfadoxine-pyrimethamine) are a major cause for concern. Although effective drugs are available, they are largely too expensive for routine use. The present article reviews the ways in which clinical pharmacology has contributed to the identification of new drugs and strategies for malaria.

Introduction

Malaria has always been a major killer of populations throughout the tropics. During the last century, it was marked out as a problem by colonial authorities and military strategists, and great advances were made in understanding its biology and developing methods of control. Indeed, in the latter half of the 20th century the combination of potent insecticides and cheap drugs offered the possibility of global eradication, for a fleeting moment. However, malaria still remains one of the largest global health care problems of the 21st century. Of the four species of human malarial parasite, Plasmodium falciparum is remarkable for its high case–fatality rate and alarming development of resistance to antimalarial drugs. This parasite will be the focus of the present article.

Sub-Saharan Africa bears the brunt of malarial mortality. There is a wide range of transmission conditions, from stable, endemic areas (where most of the population lives) to areas of infrequent parasite exposure [1]. In endemic conditions, functional immunity is acquired early in life and over 75% of mortality affects children less than 5 years of age. The ‘cost’ of developing population immunity is enormous: there were about 765 000 annual malaria deaths among children living in stable, endemic areas of Africa in 1995 [1]. In addition, pregnant mothers exposed to malaria infection suffer increased risks of severe anaemia, while the unborn child, if it survives, is often born with low birth weight; about 25% of all neonatal mortality is mediated through low birth weight consequent upon malaria infection during pregnancy [2]. Africa includes the majority of the world's poorest countries, and these are often unable to finance basic services and sustainable infrastructure. In global terms, malaria, poverty and development are intrinsically linked [3], and sub-Saharan Africa epitomises this vicious cycle. At a time when conflicts, displaced populations, human immunodeficiency virus (HIV) and global economics threaten the fragile livelihoods of most rural population,s there is growing evidence that, since the mid-1980s, the burden from malaria has been increasing [4].

The drugs used for severe malaria syndromes (quinine and the artemisinin group) largely retain efficacy in Africa. In sharp contrast, there is an impending disaster because of resistance to those inexpensive drugs traditionally employed for ‘outpatient malaria’. Clinical failure after a course of chloroquine (CQ) now exceeds 25% by a wide margin in much of East Africa, and the situation is worsening in parts of West Africa too. Critically, resistance to sulfadoxine-pyrimethamine (SP), which several countries now use as first-line, is developing apace; it seems likely that this drug will be redundant within 5 years in parts of East Africa. Many effective drugs are ruled out because of their high cost (for example atovaquone–proguanil), and alternative first-line drugs (such as amodiaquine or oral quinine) present difficulties. Artemisinin combination therapy (ACT) has been strongly suggested as the correct strategy for Africa, but immense hurdles (of cost, access and political will) remain.

Current drugs for uncomplicated malaria in Africa

Chloroquine and amodiaquine

Chloroquine (CQ) remains the treatment of choice for P. vivax, P. ovale, P. malariae and uncomplicated falciparum malaria in those few geographical areas where this drug can still be relied on. Even in areas of high-level resistance, such as East Africa, CQ is often still the most widely used treatment and still produces a clinical response (albeit with recrudescence in a majority of patients). CQ is cheap, safe and well-tolerated but its failure to eliminate parasitaemia may eventually lead to the development of profound anaemia. The efficacy of amodiaquine is greater than that of CQ, and it remains a common second-line drug in many national malaria control programmes in Africa [5]. The combination of amodiaquine with anti-retroviral therapies (ARTs) is currently being examined under the auspices of the World Health Organization (WHO).

Sulfadoxine–pyrimethamine

In many parts of Africa a decision must soon be made to replace CQ as the first-line treatment for falciparum malaria. The switch to sulfadoxine-pyrimethamine (SP) has already been made in many countries (Malawi, the forerunner, having done so in 1993). This has the great advantages of being (i) a single dose treatment, and (ii) inexpensive. Unfortunately, resistance usually develops within a few years [6], facilitated by the slow elimination of SP from the body. Folate supplements, which often accompany malaria treatment for anaemic children, probably reduce the efficacy of SP [7]. Uganda has recently opted to use a combination of CQ + SP as its first-line treatment. It will be interesting to see what success this regimen achieves, for although there are few data to support this move, there is a logical basis:

1. despite a high prevalence of CQ resistance, the drug retains some clinical efficacy in a high proportion of patients;

2. even in the face of extensive resistance, CQ can cause a rapid fall in peripheral parasitaemia;

3. the likelihood of encountering a parasite isolate resistant to both SP and CQ is lower than that for either drug alone;

4. the cost of CQ + SP, although higher than for either drug alone, is still readily affordable in an African setting;

5. the toxicity profiles of CQ and SP differ widely, and combined use is unlikely to increase the risk of adverse drug reactions in anything other than an additive manner.

Quinine

Quinine is an effective replacement for CQ and is a drug of choice for nonimmune patients with falciparum malaria. However, it has the disadvantage that it must be taken three times a day for 7 days, tastes bitter, and predictably causes unpleasant symptoms at normal therapeutic dose, thus compliance is a major problem. In those parts of South-east Asia where parasite sensitivity to quinine is declining, and where few alternatives are available, cure rates are improved if the drug is combined with tetracycline or clindamycin.

Mefloquine

This is given as a single dose (or in divided doses 6–8 h apart to reduce the risk of vomiting), and was initially highly effective against multiresistant strains of falciparum malaria throughout the world. However, in some areas, notably in the border regions of Thailand, mefloquine resistance has developed rapidly and a combination of melfoquine with artesunate is currently used. The relatively high cost of mefloquine limits its usefulness in Africa.

Artemisinin combination therapy

During treatment with two (or more) drugs, the chance of a mutant resistant to both drugs emerging can be calculated from the product of the individual per-parasite mutation rates (assuming that the resistance mutations are not ‘linked’). The artemisinin derivatives reduce the parasite biomass by around 4 logs for each asexual cycle; this makes them the most rapidly efficacious antimalarial drugs in use [8, 9]. This rapid reduction of the parasite biomass has a major theoretical role when artemisinin derivatives are combined with another antimalarial drug; the parasite population available to develop mutations to the second drug is reduced by several log orders. Thus, when mefloquine was used in combination with ARTs in Thailand, that rate of development of mefloquine resistance was reduced. WHO recommends ACT as part of the ‘ideal’ strategy for malaria control in Africa, but there are practical concerns:

1. ACT will be relatively expensive. There is only one fixed-ratio combination, lumefantrine with artemether (coartem; Riamet), and this will be made available for US$ 2.50 per adult treatment course. While this is generous of the manufacturer (in Switzerland, the drug is selling at SFr 78.50 [US$ 57.00] for a 3-day adult course), there are still problems. Firstly, US$ 2.50 is still probably too costly. Secondly, there is concern about the stability of this price. It represents an awesome commitment by the manufacturer, unless the Global Fund can contribute large revenue costs.

2. ACT has been shown to work in an experimental setting in Thailand, but it is not clear that the same will apply in an operational African setting.

3. The artemisinins are embryotoxic in rats and rabbits, and the reproductive safety of the drug class remains under scrutiny.

The biggest current problem: case management of uncomplicated falciparum malaria in Africa

Sustainable vector control has proved an elusive tool under most endemic conditions of Africa, and a malaria vaccine is unlikely to be available for some years. Insecticide-treated bed nets do offer enormous potential to households with enough resources to buy/maintain them, but case management is likely to remain the principal means of malaria ‘control’ in Africa for some time to come. Although severe falciparum malaria is a major problem throughout Africa, it is largely unaffected by drug resistance, and quinine or the artemisinin derivatives work reliably. Perhaps paradoxically, the greatest threat at the moment is the inability of poor people to access effective and affordable therapy early in the course of an uncomplicated clinical attack (thereby hopefully preventing severe disease).

The challenge can be appreciated by realizing that the majority of countries with extensive clinical CQ resistance are still using this drug because of the severe constraints faced by national malaria control programmes (NMCPs): (i) CQ is affordable, whereas most alternatives are not; (ii) SP is also affordable but resistance develops very quickly (as discussed above); and (iii) NMCP managers are wary of committing themselves to policy changes that may prove short-lived.

Academia has a role in the search for antimalarial drugs. One such example is chlorproguanil–dapsone (CPG-DDS; Lapdap^TM), the result of 15 years of laboratory and clinical research by the Department of Pharmacology and Therapeutics at Liverpool. CPG-DDS is not yet commercially available, but a dossier was submitted to the Medicines Control Agency (by GlaxoSmithKline Pharmaceuticals in partnership with WHO and DFID) in October 2002. Daily CPG-DDS for 3 days (CPG 2.0 mg kg⁻¹ and DDS 2.5 mg kg⁻¹ daily) is an effective treatment for uncomplicated falciparum malaria in semi-immune patients, and seems to be well-tolerated. CPG-DDS will cost less than US$ 0–0.5 for a 3-day adult treatment course in the public sector. There is evidence that SP treatment of parasite strains with dhfr mutations at positions 108, 51 and 59 often results in clinical failure; in contrast, the risk of clinical failure seems lower with CPG-DDS [10]. It is also probable that CPG-DDS exerts a smaller degree of ‘selection pressure for resistance’ than SP. In line with the reasoning underpinning ACT, (discussed above), work has started on the manufacture of a chlorproguanil-dapsone-artesunate (CDA) triple-combination tablet.

There have been few examples to guide us on the thinking of national ‘decision-makers’ faced with the problem of changing first-line antimalarial drugs. It seems likely that, in the case of a new drug (such as CPG-DDS) or treatment strategy, any such decision to change policy would take several years before final implementation. The first stage of assessment would comprise submission of the dossier to the national drug regulatory authority, which would establish that the drug met agreed standards of quality, efficacy and safety. However, these efficacy and safety data are usually severely limited: (ai) the drug has been studied in the artificial setting of controlled trials (so that real-world efficacy (effectiveness) may be overestimated) and (ii) only around 2000 people will usually have taken the drug (so the safety profile will be incomplete).

Furthermore, the majority of malaria case management in Africa occurs through self-medication (using drugs on the ‘General Sales List’). This is because: (i) clinical attacks are very common; (ii) most communities regard fever as synonymous with malaria; and (iii) formal health services are often distant and resource-limited. Effective use of informal services requires an informed patient/provider population; this is rarely achieved, but there is a growing recognition that the informal sector must be included as a partner in the delivery of malaria therapeutic services. Thus the final stage in assessment of a new drug or strategy would need to demonstrate its safety and robustness as a home treatment. This would require a combination of Phase IV postmarketing surveillance with an attempt to address the following logistic realities.

The practicability of the drug regimen for unsupervised out-patient use

Treatment regimens that are either protracted (beyond 3 days treatment) or complicated (e.g. treatment with two or more separately formulated drugs) would be difficult to implement.

The cost of the drug

This is a major factor; people need to remember that CQ costs around US$ 0–0.1 for a treatment course, so even a US$ 0–0.5 drug – inexpensive by any definition – still represents a significant extra burden. Furthermore, national authorities need to be convinced that the price is going to be stable. Drugs offered at a substantially subsidized price carry the risk of future price rises if the manufacturer finds that it can not maintain the subsidy.

Stability of supply

Clearly, an NMCP would need to be convinced that an adequate drug supply would always be available (this can surface as a concern over the ART drugs that, because the source material is extracted from plants, are dependent on the many determinants of crop yield).

Safety

The safety data in a standard regulatory dossier is sufficient to visualize Type A adverse drug reactions (ADRs); these are dose–concentration-related, and usually predictable from the drug's pharmacological properties). However, such Type A ADRs are rarely a source of major clinical concern (with the exception of overdose and patient subgroups in whom pharmacokinetics are perturbed, e.g. renal or hepatic impairment). Much more worrying are TypeB ADRs, which are usually/often: (i) unrelated to dose/concentration; (ii) unpredictable from the drug's pharmacological properties; (iii) immune-mediated; (iv) more severe than Type A; and critically (v) too rare to have been assessed before market authorization (a prevalence of 1 : 10 000 users is not unusual). Large Phase IV studies are needed, in which ADR-reporting systems would be established.

Pregnancy

The risks of giving a new drug to pregnant women are daunting and so: (i) drug use in pregnancy usually happens by chance; and (ii) tentative conclusions about safety take years to evolve. We do not have the time for this serendipitous process; the failure of SP ‘intermittent presumptive treatment’ will mean increased perinatal mortality for large numbers of women. Further, for a drug to be useful for malaria control, it must be usable by both children and adults, and women are often unaware of their condition during early pregnancy, when the fetus is most vulnerable. Thus new antimalarial drugs (or strategies) must address the matter of safety in pregnancy prospectively.

Effectiveness in the real world

In general, the shorter and simpler the regimen, the better. However, even the simplest regimen can be dogged by problems: (i) if a drug frequently causes a trivial but irritating ADR, e.g. chloroquine-induced pruritus, then compliance with the ideal dose regimen may be poo; (ii) if packaging allows a 3-day regimen to be sold in smaller quantities, even though the drug may be very inexpensive, savings will often be made at the expense of efficacy; (iii) if people are confused about the regimen, then a 3-day course may be taken as a single dose, perhaps causing toxicity; and (iv) compliance with the dose regimen may be good but, if the drug causes vomiting (e.g. mefloquine), then its effectiveness will be impaired.

Stability of drug sensitivity

If selection of drug resistance is facile, as it is with the antifolate compounds, NMCP managers would need reassurance that efficacy and/or effectiveness (in the ‘real world’) is likely to be stable.

Conclusions

Falciparum malaria remains a major threat to global health, especially in Africa where drug resistance threatens a major increase in mortality and morbidity. Although effective drugs are available, there are too few examples, and they are too expensive. Furthermore, the difficulties of effecting change in national antimalarial drug policy (and implementing that policy) cannot be underestimated. To hold our ground against malaria there will need to be continued collaboration between scientists, the pharmaceutical industry and malaria control programme personnel.