Rectal Administration of Artemisinin Derivatives for the Treatment of Malaria FREE

Rectal antimalarial treatment can be a valuable public health strategy in the rural tropics, where most malaria-associated morbidity and mortality occur.¹ Use of a suppository is generally feasible when oral therapy is precluded by vomiting, prostration, or impaired consciousness, and it does not require the training and facilities needed for intravenous or intramuscular injection. Although restlessness and malaria-associated diarrhea may complicate administration, rectal dosing by non–medically trained personnel could enable early treatment of severely ill patients in remote communities before transfer for further treatment in a central facility. Because the artemisinin derivatives have a wide therapeutic margin, are active against multidrug-resistant Plasmodium falciparum, and have adequate rectal absorption,² they hold great promise in this respect. In a recent review of its tropical diseases research program, the World Health Organization (WHO) identified one such rectally administered derivative, artesunate, as having the potential to reduce mortality from complications such as cerebral malaria, especially in children, if given before the patient is able to receive definitive therapy.³

The artemisinin derivatives clear parasites more rapidly than any other class of antimalarial.⁴ Their potential clinical benefit was highlighted in a recent large-scale Asian study that compared intravenous artesunate with intravenous quinine in severe malaria and found a lower mortality rate in artesunate-treated adults.⁵ Further studies are in progress to determine whether this finding applies to African children, the group that contributes most to global malaria mortality.⁶ Nevertheless, it is unclear whether rectally administered artemisinin derivatives have comparable efficacy with parenteral artesunate. Drug disposition after rectal administration will differ from that following intravenous or intramuscular injection, a situation further complicated by the variety of formulations of artemisinin derivatives that are currently available for rectal use (Table 1). Pharmacokinetic properties may vary significantly among products, and recommended dosing schedules have largely been determined empirically.

Artemisinin and 3 artemisinin derivatives, artesunate, dihydroartemisinin, and artemether, are currently marketed in various parts of the world. All can be administered either orally or rectally, and all except dihydroartemisinin can be given intramuscularly; artesunate is the only one that can be administered intravenously⁸ Of the 4 artemisinin derivatives, dihydroartemisinin (which is the active metabolite of artesunate and artemether) has the greatest in vitro activity against P falciparum, but all are more potent than other established antimalarial drugs.⁸

Drugs used for pretransfer treatment of malaria in a remote setting need to clear circulating parasite forms rapidly, thus preventing the microvascular sequestration that can lead to life-threatening vital organ dysfunction.⁹ Measures of initial parasite clearance are, therefore, an important surrogate marker of therapeutic response. The most useful measure is parasite density expressed as a percentage of the baseline measurement at 12 and 24 hours. Alternative measures include the time to 50% and 90% reductions in parasitemia. Other pharmacodynamic markers of treatment response include total parasite clearance time, fever clearance time, and clinical and parasitological cure rates. Unfortunately, the calculation of fever clearance time is poorly standardized, making between-study comparisons difficult. Clinical and parasitological cure are conventionally evaluated over 28 days, but shorter (14-day) and longer (56-day) follow-up periods have been used. The main pharmacologic variables influencing cure rates are those determining parasite exposure to therapeutic drug concentrations, namely duration of therapy and the half-lives of the drugs used. Since the artemisinin derivatives, which have relatively short half-lives, are recommended to be used as part of combination therapy with a longer-half-life partner compound, cure rates are of secondary interest in the evaluation of effect of rectal artemisinin drugs given as sole initial therapy.

The aim of the present review was to evaluate published data on the pharmacokinetics and efficacy of rectally administered artemisinin derivatives for initial treatment of uncomplicated or severe malaria. Artesunate, the derivative with the most clinical data and the widest application in this context, is highlighted, but rectal formulations of other artemisinin drugs available in endemic areas are also included.

We searched the MEDLINE, EMBASE, Cochrane Database of Clinical Reviews, Global Health, Web of Science, and CINAHL computerized databases up to December 2006 with a strategy that used both key words and Medical Subject Heading term searches comprising (artesunate or artesunic acid, or dihydroartemisinin or dihydroqinghaosu or artemisinin or qinghaosu or artemether) and (rectal or suppository or suppositories). We contacted pharmaceutical companies for unpublished data, reviewed conference proceedings, and used reference lists from retrieved articles to identify other relevant studies. Articles published in languages other than English were translated into English. Studies could be included in the review if (1) they were human clinical studies including healthy volunteers or patients of any age, regardless of Plasmodium species or clinical status, in which participant number, age, and clinical status were specified; (2) they involved rectal administration of an artemisinin derivative; and (3) they measured either plasma drug concentrations or parasite clearance assessed from serial blood smears taken at least every 6 hours. The search strategy was conducted simultaneously and independently by 2 investigators (H.A.K. and L.M.), then cross-checked. Both single-arm and comparative trials were included. For comparative clinical trials, methodological quality was assessed independently by 2 reviewers (H.A.K. and T.M.E.D.) using the Maastricht-Amsterdam score list.¹⁰ The 11 items relating to internal validity were used, and studies fulfilling at least 6 of these criteria were considered of high quality.

Primary efficacy variables of interest included parasite density as a percentage of baseline at 12 and 24 hours and/or time to 50% reduction in parasitemia. If not reported, parasite density as a percentage of baseline at 12 and 24 hours was derived from raw data by dividing 12-hour and 24-hour parasite densities by the baseline densities, if available, or by interpolation of graphical representations. A parasite density at 12 hours of less than 60% has been used as a cut point in comparing early parasite clearance between different antimalarial regimens.¹¹ Total parasite clearance time, mortality, and reported adverse events were also included. Because raw data were not always available, measures of central tendency and variance used in the original articles were reproduced as stated rather than converted to a standardized method. Where calculations were performed on raw data, mean (± standard deviation) and (for non–normally distributed data) median (range) were used.

The pharmacokinetic variables of interest were maximal plasma concentration (C_max), time to C_max (T_max), and area under the plasma concentration–time curve (AUC). All drug concentrations were converted to nanomoles using molecular weights of 284.4, 282.4, and 298.4 Da for dihydroartemisinin, artemisinin, and artemether, respectively. When studies did not provide doses in milligrams per kilogram, these were approximated by dividing the total administered dose by either the reported mean participant body weight or, for adults, an assumed weight of 65 kg for white or African participants and 50 kg for Southeast Asian participants.

To summarize the efficacy and pharmacokinetic data for each drug, data from each study were used to generate a weighted mean for each variable according to the formula

(μ₁ × n₁ + μ₂ × n₂ + μ₃ × n₃ . . . + μ_t × n_t)/(n₁ + n₂ + n₃ . . . + n_t),

where μ is the individual study mean, n is the number of participants in the study, and t is the total number of studies included. When mean values were unavailable or could not be calculated from published data, median values were substituted for μ. Mortality data were obtained from studies of moderately severe or severe malaria.

Twenty-five studies of artesunate suppositories were identified. Of these, 2 were excluded because of absence of pharmacokinetic or efficacy end points,^12- 13 leaving 23 studies. Of these, 18 evaluated Plasmotrim Rectocaps (Mepha Pharmaceuticals, Aesch-Basel, Switzerland) administered as combinations of 50- and 200-mg suppositories.^11,14- 32 Five were unpublished (Joseph Andoh, MD, et al, unpublished data, February 10–March 19, 1998),⁷ 4 of which were sourced from a submission made by WHO to the US Food and Drug Administration in 2002,⁷ which included 2 studies detailing bioequivalence and clinical data relating to another formulation of artesunate suppositories available as 100- and 400-mg doses (WHO Tropical Disease Research and Scanpharm A/S, Birkerød, Denmark).

Fourteen studies of rectally administered artemisinin were identified.^33- 46 Three were excluded, 1 because it involved patients infected with Plasmodium vivax³³ and the others, 1 of which was unpublished,³⁴ because they provided inadequate participant details.^34- 35 Of 4 studies of dihydroartemisinin^47- 50 and 2 of artemether,^51- 52 all were included except for 1 dihydroartemisinin study with inadequate participant details.⁵⁰

Artesunate. A total of 356 artesunate-treated patients were enrolled in studies of severe malaria and 287 in studies of moderately severe infection (Table 2). For studies of severe disease, the definitions of severity varied and were sometimes poorly specified, complicating between-study comparisons. Because there was significant heterogeneity in dosing regimens for rectal artesunate, these data were dichotomized into initial doses of less than 5 mg/kg and more than 5 mg/kg. Several studies used a low-dose regimen with 1.8 to 4.4 mg/kg administered repeatedly over the first 12 hours.^{14,16,18,21,27- 28,32} These showed generally slower parasite clearance during the first 12 hours and a weighted mean total parasite clearance time that was twice as long as that seen with the higher-dose regimen.^{7,19- 20,22,24- 25,29- 30,33(and unpublished data by J. Andoh, MD, et al)} There were 6 deaths in artesunate-treated patients enrolled in studies of severe malaria (1.7%) and 2 in studies of moderately severe infection (0.7%).

Artemisinin. The artemisinin studies involved 350 patients and, with the exception of 1 African study of severely ill adults,³⁷ were performed in Vietnam or China in patients with infections ranging from uncomplicated to severe (Table 2).^{36- 37,39- 45} Few calculated (or provided data necessary to calculate) parasite density as a percentage of baseline at 12 and 24 hours. However, in the 6 studies that reported time to 50% reduction in parasitemia, the mean or median values ranged from 7 hours to 11.3 hours, comparable with that for rectal artesunate. The weighted mean mortality in artemisinin-treated patients was relatively high at 12.9% but included a study of children with cerebral malaria that reported mortality of 5%.⁴⁴

Dihydroartemisinin. There have been only 2 studies of dihydroartemisinin suppositories, involving a total of 180 patients (Table 2).^48- 49 One of these⁴⁹ showed much slower initial parasite clearance than that seen in studies of other preparations, with the mean parasite density rising to 30% above baseline at 12 hours before falling to 70% at 24 hours. The dose used in this study was relatively low (3 mg/kg) and was variable, with some patients receiving as little as 2.3 mg/kg. A similar dose was used in the second study of dihydroartemisinin,⁴⁸ but no direct comparison could be made because markers of early parasite clearance were not determined. There were no deaths from severe malaria in either of these studies.

Artemether. Only 1 trial of artemether suppositories is available⁵¹ and is summarized in Table 2.

A number of studies have directly compared rectal artemisinin drugs with conventional therapies, including 2 studies using artesunate,^11,24 4 using artemisinin,^{37,41,44- 45} and 1 each involving dihydroartemisinin⁴⁸ and artemether.⁵¹ In each of these 8 studies, the similarity of the groups at baseline, adherence to therapy, withdrawal/dropouts, and timing of outcome assessments appeared acceptable, and the short-term measures of efficacy (primarily parasite clearance) implied an intention-to-treat analysis, meaning a score of 5 of 5 for these aspects. For all except the study by Hien et al⁴¹ (in which the artemisinin suppositories became unavailable during the trial), the randomization appeared adequate, suggesting that 7 studies were of high quality (score ≥6).^{11,24,37,44- 45,48,51} Nevertheless, the study by Aceng et al⁵¹ was the only one of these that used patient blinding (with a rectal placebo), and the reporting of allocation concealment and of blinding of care providers and outcome assessors was variable, while cointerventions were often either not stated or not comparable between groups.

Barnes et al¹¹ compared rectally administered artesunate with parenteral quinine in children and adults with moderately severe malaria in Malawi and South Africa. By 12 hours, 92% of children and 96% of adults treated with rectal artesunate had achieved reductions in parasitemia to less than 60% of baseline compared with 14% and 38% of quinine-treated children and adults, respectively, a difference that was maintained at 24 hours. Children treated with rectal artesunate also had more rapid clearance of fever than quinine-treated children, but there were no statistically significant differences seen with other markers of clinical response, including time to return of ability to drink or take tablets orally. A study by Karunajeewa et al²⁴ compared rectal artesunate with intramuscular artemether, a commonly used alternative to parenteral quinine for severe malaria, in 79 children with severe malaria in Papua New Guinea. This showed statistically significant differences in parasite density as a percentage of baseline at 12 hours and times to 50% and 90% reduction in parasitemia in favor of rectal artesunate. The authors concluded from plasma drug concentration data that these differences were likely due to relatively low and erratic absorption of intramuscular artemether. There were no between-treatment differences in clinical outcomes, including measures of fever clearance and return to oral intake status.

Four studies have compared artemisinin suppositories with either intravenous quinine or parenteral artesunate.^{37,41,44- 45} The 3 using quinine as a comparator all showed significantly faster parasite clearance (times to 50% and 90% reduction in parasitemia and total parasite clearance time) in the artemisinin group.^37,41,44 However, other clinical markers, including fever clearance, coma duration, and mortality, were similar. Regardless of whether intravenous or intramuscular artesunate was used as the comparator, no significant differences were seen with rectal artemisinin for parasitological or other outcomes.

A study by Esamai et al⁴⁸ that compared dihydroartemisinin suppositories with intravenous quinine demonstrated a more rapid total parasite clearance time with the artemisinin derivative, but markers of early parasite clearance were not calculated and there was no statistically significant difference in fever clearance. Aceng et al⁵¹ compared rectally administered artemether with intravenous quinine in 103 Ugandan children with cerebral malaria. There were no significant differences between treatment groups for clinical (fever clearance time, time to regaining consciousness, and time to oral intake status) and parasitological outcomes.

Nineteen pharmacokinetic studies, 6 in healthy volunteers and 13 in adults or children with uncomplicated, moderately severe, or severe malaria, were identified and are summarized in Table 3. There was marked interindividual variability in most pharmacokinetic measures, but conventional doses of artesunate achieved an earlier T_max and higher C_max than other artemisinin derivatives. The 14 pharmacokinetic studies of rectal artesunate included healthy adult volunteers,^15,17 adults with uncomplicated malaria,¹⁶ and children with uncomplicated,^21- 22,31 moderately severe,²⁵ or severe³⁰ malaria (Table 3). No study was able to demonstrate a relationship between any pharmacokinetic variable and clinical outcome. Few studies were of sufficient size to enable examination of the effect of covariates on pharmacokinetics.

The results of 3 pharmacokinetic studies of rectal artemisinin performed in mostly male white or Vietnamese participants are summarized in Table 3.^36,38- 39 Participants were either healthy volunteers or had uncomplicated malaria. No study involved children or adults with moderate or severe disease. The study of dihydroartemisinin suppositories was performed in adults with uncomplicated malaria.⁴⁷ The study of rectal artemether⁵² used a parenteral formulation (Kunming Pharmaceuticals, Kunming, China) dissolved in arachis oil and rectally self-injected by healthy white volunteers. There is a suppository formulation of artemether,⁵¹ but its pharmacokinetic properties are unknown.

More than 1600 patients, including more than 600 children, have received a rectal artemisinin drug in published or unpublished trials (Table 2 and Table 3). Adverse events have not been reported in a standardized manner. Minor adverse events have included dizziness, transient fever occurring approximately 24 hours after parasite clearance, and gastrointestinal symptoms (nausea, vomiting, abdominal pain, constipation, or diarrhea).^{23- 24,28,34,37,43} It is unclear whether these symptoms relate to the artemisinin drugs, a coadministered partner drug, or malaria itself.

No symptoms suggestive of neurotoxicity have been described in any study evaluating a rectally administered artemisinin derivative, including those using artesunate at doses of up to 20 mg/kg^25,30 and artemisinin at doses of up to 40 mg/kg.⁴⁴ Although tenesmus has been described in up to 26% of those administered artemisinin suppositories,^34,37,43 no study has described rectal bleeding or anal irritation that would indicate a local inflammatory reaction.

Artemisinin derivatives formulated for rectal administration have the potential to be widely used in tropical countries. Their intended role is primarily as pretransfer antimalarial therapy for sick children in remote communities, but their application may extend to other contexts, even in developed countries. There is, therefore, a need for increased awareness of the pharmacologic properties and efficacy of rectally administered artemisinin compounds. It is likely that artesunate suppositories will remain the most widely prescribed drug in this respect,³ but availability, cost, and sociopolitical factors may result in an increase in use of alternative derivatives.

Similar to experience with oral and parenteral artemisinin formulations, the introduction of rectal derivatives into clinical use has not followed classic pathways of rational drug development. Rectal absorption of these compounds must be prompt and reliable if they are to have a rapid parasiticidal effect, but supportive pharmacokinetic and pharmacodynamic data have lagged behind the widespread availability of a variety of formulations that are administered using empirically derived dosing regimens. Reasons for this include the practical challenges of performing pharmacokinetic studies in representative patient samples in the rural tropics and the lack of stringent control of drug licensing in many developing countries. Because pharmaceutical factors can influence pharmacokinetic disposition, preparations of the same derivative from different manufacturers may not be bioequivalent.

The data reviewed showed mean or median T_max values of 1 to 4 hours for artesunate compared with values of 4 to 7 hours for artemisinin and dihydroartemisinin and 3 hours for artemether. Similarly, artesunate administered at more than 10-mg/kg doses resulted in mean or median C_max and AUC values 3 to 10 times those achieved with artemisinin (7-12 mg/kg), dihydroartemisinin (3 mg/kg), or artemether (5 mg/kg). These values suggest a therapeutic advantage for artesunate, but more data are needed for dihydroartemisinin and artemether. Although it is unclear whether earlier and higher plasma concentrations confer therapeutic advantage, it is notable that initial parasite clearance was slower for low-dose artesunate regimens (weighted mean parasite density as a percentage of baseline at 12 hours, 62.3% for low-dose regimens vs 16.1% for high-dose regimens; Table 2), with the slowest clearance in a study of low-dose rectal dihydroartemisinin.⁴⁹

The most striking aspect of the pharmacokinetic studies reviewed was the degree of interindividual variability in pharmacokinetic measures. The bioavailability of artesunate has been reported to be as low as 6%,²⁵ and coefficients of variation for C_max and AUC are also wide for the other rectally administered artemisinin derivatives. This implies that a small proportion of patients are at risk of subtherapeutic drug concentrations. Because even very low plasma concentrations are likely to exceed the parasite minimal inhibitory concentration,⁸ the clinical significance of this variability may be minor. In addition, even with close monitoring, the possibility exists that suppositories are expelled, a potentially serious situation that argues for multiple dosing in the first 24 hours.²²

The artemisinin derivatives appear to be safe and well tolerated,^55- 56 and the present review suggests that there are no additional concerns associated with rectal administration. Although tenesmus and a burning sensation were reported in some studies of rectal artemisinin,⁴⁴ there has been no evidence suggesting proctitis of the type that occurs with rectal quinine.⁵⁷ The brain-stem lesions observed in laboratory animals receiving prolonged supratherapeutic doses of lipid-soluble artemisinin derivatives⁵⁸ have never been convincingly demonstrated in humans, and it is reassuring that there were no descriptions of neurotoxic symptoms in the approximately 1600 participants, more than one third of whom were children, treated with rectal artemisinin compounds in the studies reviewed herein. This includes doses of up to 20 mg/kg of artesunate and 40 mg/kg of artemisinin.^25,30,44 It is of interest that higher doses of artesunate may be associated with reduced bioavailability,²⁵ which could help protect against possible toxic effects.

A number of comparative trials provide some evidence that rectal preparations may initiate parasite clearance more rapidly than conventional treatment, including parenteral quinine and artemether.^{11,24,37,41,44- 45,48,51} Recent experience with intravenous artesunate suggests that prompt parasite clearance is associated with reduced mortality in severe malaria in adults.⁴ None of the comparative trials of rectal artemisinin derivatives were powered to assess mortality as an end point, although it is noteworthy that other clinical markers (including fever clearance and coma duration) were similar to those with the comparator drugs. Because of the large sample sizes required for a noninferiority study, it is unlikely there will ever be a trial comparing a rectal artemisinin with conventional treatment for severe malaria using mortality as an end point. Therefore, markers of early parasite clearance and pharmacokinetic measures (including their variability) will be the most useful end points in future trials.

The present study had limitations. First, our weighted mean estimates of efficacy and pharmacokinetic variables were often from small numbers of studies with incomplete data. This made formal assessment of statistical heterogeneity difficult. Our derived results must be interpreted with caution as a result, but the summary data from individual studies cited in the tables support our overall conclusions. Second, the definition of severe (including cerebral) malaria included a variable number of components and different severity cut points. Although the pharmacokinetic properties of the artemisinin drugs do not appear to be influenced by disease severity,⁵⁹ a greater number of studies and more uniform definition of severity would have facilitated an analysis of parasite clearance measures by clinical status.

Available data support artesunate at doses of more than 10 mg/kg and artemisinin at 12 mg/kg as having good clinical efficacy regardless of factors such as age, sex, and race/ethnicity. Artesunate appears to be the better option given its more rapid absorption and higher plasma concentrations at these doses. However, the present review highlights the need for more pharmacologic and efficacy data for all rectal artemisinin drugs, including studies involving (1) head-to-head comparisons of the initial clinical efficacy of different formulations and dose regimens (especially involving dihydroartemisinin and artemether); (2) pharmacokinetic analysis including bioavailability and its predictors and effect on parasite clearance; and (3) well-characterized severely ill patients with intravenous artesunate as a comparator. Given the concerns regarding lower limits of bioavailability and pending further research particularly in the context of severe malaria, prescribing should be consistent with current WHO guidelines that restrict use to pretransfer treatment when oral therapy is not possible and where injectable antimalarial drugs are unavailable, followed by prompt definitive treatment (intravenous artesunate/quinine or a full course of an approved oral artemisinin-based combination therapy) as dictated by the clinical state of the patient.