Importance of the long-acting partner drug in artemisinin-based combination therapy

Abstract

The 1st African Health Research Organization International Malaria Symposium on Clinical Pharmacology of Antimalarial Drugs collected approximately 60 health professionals, scientists, policy makers and nongovernmental organization representatives from Africa, Europe and the USA for updates on recent developments in malaria therapy. It was the first African Health Research Organization symposium in Africa aimed at taking an African leadership in the fight against malaria. The intention is to start a tradition of annually recurring symposia that will eventually grow to become a leading international event in malaria research. Apart from scientific presentations, substantial time was dedicated to discussions and brainstorming, with a view to developing tools that can realistically be used to address challenges relating to all aspects of malaria treatment and control. The meeting was funded partly by the Medicines for Malaria Venture and Dafra Pharma International Ltd., Belgium, both of which were represented by some of the speakers.

Artemisinin-based combination therapy (ACT) for malaria has been advocated by the WHO since 2006 and has been widely accepted by policy makers throughout Africa. The principle behind ACT is the rapid elimination of parasites by the fast-acting artemisinin, followed by the clearing up of the few remaining parasites by a longer acting partner drug. In her opening presentation, F Owusu-Antwi (WHO, Accra, Ghana) gave examples of how the WHO continuously monitors the effect of ACT through surveillance of resistance and, importantly, also through campaigns to ban the marketing of artemisinin monotherapy. Although several ACT combinations exist, there is still an interest in optimizing the choice of both artemisinin and partner drugs. The WHO recommends that resistance against the partner drug should be present in no more than 25% of parasite isolates. However, ACT treatments with much more widespread resistance against partner drugs have been effective in some trials.

Two new ACT combinations that differed in the choice of partner drug were presented. Bruno Jansen (Dafra Pharma, Belgium) presented results from a recent, so far unpublished, multicenter trial of the combination of artesunate (AS) and sulfamethoxypyrazine (SM) plus pyrimethamine (P) tested against artemether (AM) and lumefantrine (L). SMP has a similar mode of action to sulfadoxine–pyrimethamine (SP) but has a longer half-life and lower protein binding. The presented study had one AM–L arm and two AS–SMP arms, both receiving three doses of a combination of SM 500 mg plus P 30 mg plus AS 200 mg (adult dose, reduced in children according to bodyweight). In one arm, doses were given at 0, 6 and 24 h, in the other at 0, 24 and 48 h. The sample sizes were 458 (AS–SMP, 24 h), 478 (AS–SMP, 48 h) and 450 (AM–L). The prevalence of SP resistance in the different study sites was 50, 30 and 15% in Rwanda, Cameroon and Sudan plus Mali, respectively. Despite the high prevalence of resistance to SP, which is closely related to the partner drug SMP, day 28 PCR-adjusted cure rates were 99.5% for AS–SMP compared with 99.8% for AM–L, confirming the favorable outcome found in a previous trial [1]. Other clinical trials present conflicting data on the risk of treatment failure in areas with a high prevalence of resistance against the long-acting ACT partner drug. However, based on the presented data, Jansen wished to challenge the present requirement by the WHO for higher than 75% sensitivity to the partner drug.

In a controversial subsequent session, Jansen advocated for the use of AS plus SMP as a sort of ‘wonder drug’ for use in intermittent presumptive treatment (IPT) of infants and pregnant women with additional effects on schistosomiasis, meningococci and Haemophilus. This spurred a heated debate that strongly discouraged the use of ACT for IPT owing to worries concerning resistance developing against artemisinins.

Larry Fleckenstein (University of Iowa, IA, USA) presented pharmacokinetic data from Phase I [2] and Phase II [Fleckenstein L, Unpublished Data] trials of the ACT combination AS plus pyronaridine (PYR). These studies were performed in collaboration with the South Korean company Shin Poong Pharm. Inc., under the auspices of Medicines for Malaria Venture (MMV) [101]. PYR has been used for monotherapy of chloroquine (CQ)-resistant Plasmodium falciparum and for Plasmodium vivax malaria. The studies showed that PYR had a large volume of distribution (19,000 l) and was accumulated in red blood cells. There were several estimates of the elimination half-life, of which the most well documented data showed a half-life of 16.4 days. Administration with food resulted in a 20% increase in AUC and C_max of PYR, but while this was statistically significant it was deemed clinically irrelevant. No significant interaction was found between PYR and AS on C_max and AUC. The Phase II study in patients with uncomplicated malaria showed C_max lower than in healthy volunteers, most probably due to disease-mediated changes in the volume of distribution.

Results of safety and efficacy trials will be presented elsewhere but preliminary analyses were generally satisfactory. Principle adverse events included gastrointestinal disturbances but little redosing was required due to vomiting.

Phase III studies just finishing in Southeast Asia and East and West Africa will address the effects of age, ethnicity, parasite density, hemoglobinopathies and other cofactors that may influence the use of AS–PYR.

Owing to cancellation of several of the scheduled presentations, Stephan Duparc was invited to give a summary of ongoing and past studies supported by MMV. The presentation included data from two recent, not yet published, Phase III studies on dihydroartemisinin and piperaquine (Eurartesim^®) [102]. The trials were conducted in collaboration with Sigma-Tau, Italy, Chongqing Holley, China and Oxford University, UK. The first study was performed in pediatric patients (1533 African children), and Eurartesim was tested against AM–L. The second study was conducted in 1150 Asian adults where Eurartesim was tested against AS plus mefloquine. Based on the positive outcome of the trials, MMV expects to submit applications for registration in 2009. The MMV aims to roll out three next-generation ACTs by the year 2010 aimed at obtaining cure with a single dose of treatment and effective eradication of the transmissible stage of the malaria parasites, the gametocyte stage.

Role of the artemisinin component in antimalarial combination therapy

Jean-Bosco Ouegraogo (IRSS, Bobo-Dioulasso, Burkina Faso) presented data challenging the uncritical promotion of ACT. Until 2005 the recommended treatment of uncomplicated malaria in Burkina Faso was CQ or amodiaquine (AQ) with SP as second-line treatment. In 2005, this gave way to ACT either as AM–L or AS–AQ. The decision was made despite the high prevalence of AQ treatment failure, ranging from 8 to 19%, in various parts of the country. Studies conducted after the policy change [3] show consistently similar clinical response to AQ plus SP and AM–L. However, the risk of reinfection was substantially lower in the AQ plus SP group (four out of 233 vs 25 out of 245 patients). Thus, the use of non-ACT antimalarial drug combinations may still have a place in African countries and deserves continued focus.

George Obeng Adjei (Korle-Bu Teaching Hospital, Accra, Ghana) presented data on the efficacy, safety and pharmacokinetics of AS–AQ and AM–L. Both ACT combinations showed similar effect in a trial in uncomplicated pediatric malaria [4] and no differences could be found in the occurrence of adverse events. Notably, detailed neurological assessment showed no evidence of side effects during a 1-year follow-up period. In particular, repeated audiometry demonstrated an increased hearing threshold during the acute malaria attack that was fully reversible 1 year after treatment. This pattern was also found in a control group receiving AQ alone, suggesting that the malaria infection itself was the cause of the hearing impairment. However, it is still necessary to monitor possible neurological side effects of artemisinins.

Godswill Anyasor (Babcock University, Ilisan Remo, Nigeria) presented a study that gave rise to concern regarding the widespread use of artemisinins based on the fact that artemisinins may have cytotoxic effects in human T cells. AS had pronounced effects on rat liver mitochondrial membrane permeability transition (MMPT) in vitro and in vivo. At concentrations in vivo equivalent to those used for antimalarial treatment, MMPT was increased with resultant changes in mitochondrial morphology. This could lead to programmed cell death (apoptosis) of the affected cells, which causes particular concern regarding the possible use of artemisinins in pregnancy.

Role of the African context in the management of malaria

Typical African diets are poor in fat, which is important for the absorption of several antimalarial compounds. Issaka Sagara (University of Bamako, Bamako, Mali) presented data on the bioavailability of L in this context. Data from a number of African countries showed that the daily fat intake was well above the 1.2 g/day needed for appropriate absorption of L [5]. This corresponds with the daily experience of a high cure rate with AM–L treatment, even when administered unsupervised. The following discussion gave room for a number of very practical and useful suggestions on the management of the sick, often nauseated and anorectic child.

A particular challenge for the use of ACT is the fact that the main target group for antimalarial treatment is children under 5 years of age. There is, thus, a need to document the effect of drug suspensions or soluble tablets. Sagara presented data from an MMV- and Novartis-sponsored randomized noninferiority trial comparing ordinary crushed tablets (n = 394) and rapidly dissolvable tablets (n = 388) of A–L in pediatric malaria patients [6]. The study confirmed that A–L continues to have an efficacy of approximately 98% in all study sites (Mali, Benin and Kenya [three sites], Tanzania [two sites] and Mozambique), and no difference could be found between the treatment arms. Several in the audience questioned the usefulness of such a trial, but it became clear that this was a requirement for registration of the new drug formulation.

Elizabeth Juma (Kenya Medical Research Institute, Nairobi, Kenya) presented a Dafra Pharma-sponsored trial comparing A–L administered as either crushed tablets (n = 125) or as suspension (n = 122). Tablets were given at standard dosage and intervals, whereas suspensions were given once daily for 3 days at the same total dosage as the tablets. While the study did not find any difference in efficacy or adverse events between the arms, the efficacy was surprisingly low in the study area close to Kisumu, Kenya. Day 28 PCR-corrected cure rates were between 93 and 95%, which is below the level recommended by the WHO.

The meeting also included presentations regarding the adjunct therapy of severe malaria, fitness of drug-resistant parasites, pre-erythrocytic malaria vaccines and a more philosophical presentation on taking laboratory research into practice. However, most rewarding was probably the vibrant discussions and enthusiasm by the participants who clearly had broad clinical experience to share. The organizers plan to make the symposium a returning annual event, which may be extremely useful if the novelty of presentations and the fruitful discussions can be maintained.

Financial & competing interests disclosure

The author has no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.